Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide

In the paper

“Remarkably, these structurally divergent small molecules all directly engage a substrate receptor-less CUL4 E3 ligase complex by binding to its substrate adaptor component, DDB1, whilst simultaneously interacting with and thereby recruiting CDK12 in complex with cyclin K.”

What the sources say

• Disputed

  The Results section, “In Vitro Reconstitution of RBM39 Ubiquitination” (page unavailable), explicitly identifies DCAF15 as the substrate receptor and DDB1 as the adaptor, contrary to the claimed receptor-less complex. The Discussion (page unavailable) reports sulfonamide-dependent recruitment of RBM39 to CRL4-DCAF15, not recruitment of CDK12–cyclin K through binding to DDB1. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [182] Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep. 29, 1499–1510.e6 (2019). sourceExperimental — accuracy not yet measured
• Disputed

  The Abstract and Discussion describe aryl-sulfonamides recruiting RBM39 through the substrate receptor DCAF15, not recruiting CDK12–cyclin K to a receptor-less CUL4 complex. The Results section on the DCAF15 structure says DCAF15 binds DDB1; it does not say the small molecules bind DDB1. Searches for CDK12 and cyclin K found no passage addressing either protein. (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  cites [183] Faust, T. B. et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 16, 7–14 (2020). sourceExperimental — accuracy not yet measured
• Not checked yetcites [184] Du, X. et al. Structural basis and kinetic pathway of RBM39 recruitment to DCAF15 by a sulfonamide molecular glue E7820. Structure 27, 1625–1633.e3 (2019). source

In the paper

“In this population, lenalidomide and dexamethasone are typically combined with a proteasome inhibitor, such as bortezomib28, and/or the CD38-targeting monoclonal antibody daratumumab29.”

What the sources say

• ?Could not verify

  The Introduction and Methods describe lenalidomide plus rituximab for relapsed or refractory indolent lymphoma, not treatment of newly diagnosed multiple myeloma. A search for lenalidomide, dexamethasone, and bortezomib in newly diagnosed myeloma found no passage supporting the regimen attributed to this source. The bortezomib study listed in the References also concerns follicular lymphoma. (LLM, conf=0.75)

  cites [28] Leonard, J. P. et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J. Clin. Oncol. 19, 1188–1199 (2019). sourceExperimental — accuracy not yet measured
• Not checked yetcites [29] List, A. et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N. Engl. J. Med. 355, 1456–1465 (2006). source

In the paper

“Data from a number of in vitro studies support the hypothesis that thalidomide analogues synergize with dexamethasone49,50, proteasome inhibitors51,52, histone deacetylase inhibitors53,54 and a variety of other agents”

What the sources say

• Partly supported

  The Abstract reports pomalidomide activity in lenalidomide-resistant cell lines and cites preclinical work; the References list a study of synergistic responses to pomalidomide plus dexamethasone in preclinical models. This supports the dexamethasone part to which this citation is attached, but Siegel et al. do not themselves report in vitro synergy experiments. The citations following proteasome and histone deacetylase inhibitors attach to other sources. (LLM, conf=0.82)

  cites [49] Siegel, D. S. et al. Pomalidomide plus low‐dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure. Br. J. Haematol. 188, 501–510 (2019). sourceExperimental — accuracy not yet measured
• Supported

  This source is cited alongside the dexamethasone portion of the sentence. Its Introduction states that pomalidomide, a thalidomide analogue, and dexamethasone have synergistic antiproliferative effects in lenalidomide-resistant myeloma cells. The proteasome-inhibitor and histone-deacetylase-inhibitor portions carry different citations and are not attributed to this source. (LLM, conf=0.93)

  cites [50] Richardson, P. G. et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood 123, 1826–1832 (2014). source
• Not checked yetcites [51] Lacy, M. Q. et al. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood 118, 2970–2975 (2011). source

In the paper

“CRBN expression levels in patient samples has been positively associated with sensitivity to thalidomide analogues in some studies149–154, but not in others155,156.”

What the sources say

• ?Could not verify

  The citation is attached to the claim that some studies did not find a positive association between CRBN expression in patient samples and sensitivity to thalidomide analogues. The CRBN-associated mutations section reports expression-dependent sensitivity in a cell line, while the Discussion addresses mutations in patient samples; neither reports a study finding no association between patient-sample CRBN expression and drug sensitivity. Pages were not provided in our copy. (LLM, conf=0.75)

  cites [149] Kortüm, K. M. et al. Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood 128, 1226–1233 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  The paper’s main text reports lower cereblon levels when patients become resistant to lenalidomide or pomalidomide, and its References section lists studies associating high CRBN expression with better outcomes in treated patients. Our copy does not establish the other half of the claim: that some patient studies found no positive association. The paper primarily investigates gene mutations rather than comparing those expression studies. (LLM, conf=0.82)

  cites [150] Thakurta, A. et al. Absence of mutations in cereblon (CRBN) and DNA damage-binding protein 1 (DDB1) genes and significance for IMiD therapy. Leukemia 28, 1129–1131 (2013). sourceExperimental — accuracy not yet measured
• Supported

  The section on exon 10-spliced CRBN transcripts states that pretherapy CRBN expression did not correlate with subsequent pomalidomide response and that the authors confirmed this result using RNASeq. This supports citing the paper for the ‘but not in others’ portion of the sentence; it does not establish the positive associations reported by other studies. (LLM, conf=0.91)

  cites [151] Gooding, S. et al. Multiple cereblon genetic changes associate with acquired resistance to lenalidomide or pomalidomide in multiple myeloma. Blood https://doi.org/10.1182/blood.2020007081 (2020). source
• Supported

  The Results and Conclusion report that CRBN-positive myeloma samples were associated with better responses to lenalidomide- and thalidomide-based regimens. This supports the positive-association part of the citing sentence; the contrasting studies are assigned separate citations. (LLM, conf=0.94)

  cites [152] Huang, S.-Y. et al. Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma. Ann. Hematol. 93, 1371–1380 (2014). source
• Supported

  The Results report no association between Cereblon expression and response, progression-free survival, or overall survival with the lenalidomide-containing REP regimen. This supports the ‘but not in others’ part of the citing sentence, while the paper separately reports reduced Cereblon protein levels with acquired lenalidomide resistance. The supplied copy does not provide page numbers. (LLM, conf=0.90)

  cites [153] Franssen, L. E. et al. Cereblon loss and up-regulation of c-Myc are associated with lenalidomide resistance in multiple myeloma patients. Haematologica 103, e368–e371 (2018). source
• Supported

  The Summary (p. 3) reports a significant positive association between baseline CRBN expression and response to lenalidomide in 49 patients with multiple myeloma. This source supports the positive-association part of the citing sentence; the sentence assigns the contrasting negative findings to other citations. (LLM, conf=0.93)

  cites [154] Heintel, D. et al. High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone. Br. J. Haematol. 161, 695–700 (2013). source
• Not checked yetcites [155] Jonasova, A. et al. High level of full-length cereblon mRNA in lower risk myelodysplastic syndrome with isolated 5q deletion is implicated in the efficacy of lenalidomide. Eur. J. Haematol. 95, 27–34 (2014). source
• Supported

  Results §3.2 reports that none of the patients with the lowest CRBN expression responded to IMiD therapy, while response rates were higher at greater expression levels. The Discussion likewise describes a correlation between CRBN expression and response. This paper supports the positive-association side of the citing sentence; the contrasting finding is attributed to other citations. (LLM, conf=0.92)

  cites [156] Schuster, S. R. et al. The clinical significance of cereblon expression in multiple myeloma. Leukemia Res. 38, 23–28 (2013). source

In the paper

“Maintenance lenalidomide following induction therapy with or without autologous haematopoietic stem cell transplantation (auto-HSCT) is also a standard of care for patients with MM30,31.”

What the sources say

• Not checked yetcites [30] FDA. FDA grants accelerated approval to pomalidomide for Kaposi sarcoma. US Food & Drug Administration https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pomalidomide-kaposi-sarcoma (2020).
• Not checked yetcites [31] Richardson, P. G. et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100, 3063–3067 (2002). source

In the paper

“in del(5q) MDS cells, lenalidomide mediates the CRBN-dependent ubiquitination and degradation of casein kinase I isoform α (CK1α)15.”

What the sources say

• Not checked yetcites [15] Krönke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015). source

In the paper

“All pharmacologically active derivatives of thalidomide contain a glutarimide ring that directly binds within a conserved pocket on the surface of CRBN17”

What the sources say

• Not checked yetcites [17] Fischer, E. S. et al. Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49–53 (2014). source

In the paper

“In 2002, a phase I trial of lenalidomide monotherapy revealed promising signs of efficacy in patients with relapsed and/or refractory (R/R) MM, about 50% of whom had previously received thalidomide23.”

What the sources say

• Not checked yetcites [23] Choueiri, T. K. et al. Phase II study of lenalidomide in patients with metastatic renal cell carcinoma. Cancer 107, 2609–2616 (2006). source

In the paper

“which serves as a substrate receptor component of the cullin-RING E3 ubiquitin ligase complex 4 (CRL4) comprising cullin-4 (CUL4), DNA damage-binding protein 1 (DDB1) and E3 ubiquitin-protein ligase RBX1”

In the paper

“By contrast, lenalidomide has demonstrated a clear OS advantage (~88% versus 80% at 3 years) with a hazard ratio for death of approximately 0.6030,31,33,34.”

What the sources say

• Not checked yetcites [30] FDA. FDA grants accelerated approval to pomalidomide for Kaposi sarcoma. US Food & Drug Administration https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pomalidomide-kaposi-sarcoma (2020).
• Not checked yetcites [31] Richardson, P. G. et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100, 3063–3067 (2002). source
• Not checked yetcites [33] Richardson, P. G. et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 108, 3458–3464 (2006). source

In the paper

“IKZF1, IKZF3 and CK1α are required for MM or MDS cell survival (BOX 2)”

What the sources say

• Not checked yetcites [16] Fink, E. C. & Ebert, B. L. The novel mechanism of lenalidomide activity. Blood 126, 2366–2369 (2015). source

In the paper

“In this subset of patients, maintenance therapy with proteasome inhibitors alone or in combination with lenalidomide seems to be more effective than single-agent lenalidomide34,35.”

What the sources say

• Not checked yetcites [34] Benboubker, L. et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N. Engl. J. Med. 371, 906–917 (2014). source
• Not checked yetcites [35] Richardson, P. G. et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116, 679–686 (2010). source

In the paper

“In patients with newly diagnosed MM, ORRs are even higher, with up to 90% of patients responding to the combination of lenalidomide and dexamethasone26.”

What the sources say

• Not checked yetcites [26] Weber, D. M. et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N. Engl. J. Med. 357, 2133–2142 (2007). source

In the paper

“Clinical testing revealed the efficacy and tolerability of thalidomide in patients with multiple myeloma (MM)8–10”

What the sources say

• Not checked yetcites [8] Singhal, S. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 341, 1565–1571 (1999). source
• Not checked yetcites [9] Rajkumar, S. V. et al. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J. Clin. Oncol. 20, 4319–4323 (2002). source
• Not checked yetcites [10] Rajkumar, S. V. et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J. Clin. Oncol. 24, 431–436 (2006). source

In the paper

“In the 1990s, thalidomide was reconsidered as an anticancer agent7.”

What the sources say

• Not checked yetcites [7] D’Amato, R. J., Loughnan, M. S., Flynn, E. & Folkman, J. Thalidomide is an inhibitor of angiogenesis. Proc. Natl Acad. Sci. USA 91, 4082–4085 (1994). source

In the paper

“thereby establishing selective degradation of disease-relevant proteins as the unexpected mechanism underlying the anticancer effects of thalidomide analogues16.”

What the sources say

• Not checked yetcites [16] Fink, E. C. & Ebert, B. L. The novel mechanism of lenalidomide activity. Blood 126, 2366–2369 (2015). source

In the paper

“In 2010, thalidomide was found to directly bind to the protein cereblon (CRBN)14”

What the sources say

• Not checked yetcites [14] Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010). source

In the paper

“Thalidomide, lenalidomide and pomalidomide are currently FDA approved in a variety of clinical settings, including MM, NHL and MDS as well as Kaposi sarcoma (KS)19–22.”

What the sources say

• Not checked yetcites [19] Ramsay, A. G. et al. Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J. Clin. Invest. 118, 2427–2437 (2008).
• Not checked yetcites [20] Hagner, P. R. et al. CC-122, a pleiotropic pathway modifier, mimics an interferon response and has antitumor activity in DLBCL. Blood 126, 779–789 (2015). source
• Not checked yetcites [21] Luptakova, K. et al. Lenalidomide enhances anti-myeloma cellular immunity. Cancer Immunol. Immunother. 62, 39–49 (2013). source
• Not checked yetcites [22] Muller, G. W. et al. Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity. J. Med. Chem. 39, 3238–3240 (1996). source

In the paper

“Each thalidomide analogue is distinguished by variations on a phthaloyl ring moiety that dictate binding to a limited number of neosubstrate proteins.”

In the paper

“In 2013, thalidomide analogues were discovered to exert their therapeutic effects by acting as a molecular glue to recruit disease-relevant neosubstrate proteins to an E3 ubiquitin ligase, resulting in neosubstrate ubiquitination and, ultimately, proteasomal degradation11–13.”

What the sources say

• Not checked yetcites [11] Krönke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2013). source
• Not checked yetcites [12] Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2013). source
• Not checked yetcites [13] Gandhi, A. K. et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4 CRBN. Br. J. Haematol. 164, 811–821 (2013). source

In the paper

“Thus, the activity and toxicity profiles of each thalidomide analogue are determined by their unique polypharmacology: the combinatorial degradation of multiple neosubstrates by the ubiquitin-proteasomal system (UPS; BOX 1 and BOX 2).”

In the paper

“given that proteasome inhibitors antagonize lenalidomide-induced protein degradation11,12,55.”

What the sources say

• Not checked yetcites [11] Krönke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2013). source
• Not checked yetcites [12] Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2013). source
• Not checked yetcites [55] Stewart, A. K., Richardson, P. G. & San-Miguel, J. F. How I treat multiple myeloma in younger patients. Blood 114, 5436–5443 (2009). source

In the paper

“Pomalidomide is most often used in combination with dexamethasone, either alone or as part of triplet regimens with a variety of other anti-myeloma agents, including bortezomib45, daratumumab46 or elotuzumab47.”

What the sources say

• Not checked yetcites [45] Wang, M. et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 112, 4445–4451 (2008). source
• Not checked yetcites [46] Stewart, A. K. et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 372, 142–152 (2015). source
• Not checked yetcites [47] Moreau, P. et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 374, 1621–1634 (2016). source

In the paper

“Lenalidomide has also safely been combined with other anti-CD20 antibodies, such as obinutuzumab, in the treatment of B cell lymphomas (for example, R/R FL)80.”

What the sources say

• Not checked yetcites [80] Badoux, X. C. et al. Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J. Clin. Oncol. 31, 584–591 (2013). source

In the paper

“In addition, patients with R/R chronic lymphocytic leukaemia (CLL) receiving R2 have a ORR of >65%78”

What the sources say

• Not checked yetcites [78] Morschhauser, F. et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N. Engl. J. Med. 379, 934–947 (2018). source

In the paper

“lenalidomide monotherapy triples PFS when used as a maintenance regimen following standard second-line chemotherapy (median PFS 33.9 months versus 9.2 months with placebo; HR 0.40, 95% CI 0.29–0.55; P <0.0001)79.”

What the sources say

• Not checked yetcites [79] Ruan, J. et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N. Engl. J. Med. 373, 1835–1844 (2015). source

In the paper

“The most worrisome adverse effect observed in studies of lenalidomide maintenance therapy is an up to six-fold increase in the risk of second primary malignancies, in particular, MDS and acute myeloid leukaemia (AML): 5.3% versus 0.8% with placebo or observation34.”

What the sources say

• Not checked yetcites [34] Benboubker, L. et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N. Engl. J. Med. 371, 906–917 (2014). source

In the paper

“In addition to MM, other mature B cell malignancies seem to depend upon IKZF1 and IKZF3 for maintenance of cancer cell phenotype and survival.”

In the paper

“however, in no malignancies are these agents active without evidence of direct cytotoxicity to the cancer cells.”

In the paper

“Nevertheless, adoption of lenalidomide for the treatment of indolent lymphomas and CLL has been limited, largely owing to the availability of other highly active therapies for these diseases.”

In the paper

“The success of lenalidomide led to the development of pomalidomide, which has demonstrated efficacy in around a third of patients with lenalidomide-refractory MM42–44.”

What the sources say

• Not checked yetcites [42] Goldschmidt, H. et al. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia 32, 383–390 (2017). source
• Not checked yetcites [43] Palumbo, A. et al. Continuous therapy versus fixed duration of therapy in patients with newly diagnosed multiple myeloma. J. Clin. Oncol. 33, 3459–3466 (2015). source
• Not checked yetcites [44] Madan, S. et al. Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma. Blood 118, 1763–1765 (2011). source

In the paper

“Notably, no relevant clinical activity has been observed in trials encompassing a variety of solid tumour types, including immunotherapy-sensitive tumours such as renal cell carcinoma63 and melanoma64.”

What the sources say

• Not checked yetcites [63] Palmer, A. C. & Sorger, P. K. Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy. Cell 171, 1678–1691.e13 (2017). source
• Not checked yetcites [64] Orlowski, R. Z. et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J. Clin. Oncol. 20, 4420–4427 (2002). source

In the paper

“Thus, despite clear effects on immune cell function and clinical activity against erythema nodosum leprosum and KS22, no strong data support a primarily immunomodulatory mechanism of antitumour action of thalidomide analogues.”

What the sources say

• Not checked yetcites [22] Muller, G. W. et al. Structural modifications of thalidomide produce analogs with enhanced tumor necrosis factor inhibitory activity. J. Med. Chem. 39, 3238–3240 (1996). source

In the paper

“Meta-analyses suggest that indefinite maintenance therapy is superior in terms of survival outcomes36”

What the sources say

• Not checked yetcites [36] Facon, T. et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N. Engl. J. Med. 380, 2104–2115 (2019). source

In the paper

“Co-occurring TP53 mutations probably also explain why patients with del(5q) in combination with a complex karyotype or in the setting of AML do not respond to lenalidomide99.”

What the sources say

• Not checked yetcites [99] Martinez-Høyer, S. et al. Loss of lenalidomide-induced megakaryocytic differentiation leads to therapy resistance in del(5q) myelodysplastic syndrome. Nat. Cell Biol. 22, 526–533 (2020). source

In the paper

“Lenalidomide has activity in this disease by inducing degradation of CK1α, the protein product of the haploinsufficient gene CSNK1A1 that is located on the common deleted region of chromosome 5q, leading to activation of p53 and subsequent apoptosis15,96.”

What the sources say

• Not checked yetcites [15] Krönke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015). source
• Not checked yetcites [96] List, A. et al. Efficacy of lenalidomide in myelodysplastic syndromes. N. Engl. J. Med. 352, 549–557 (2005). source

In the paper

“Lenalidomide monotherapy has produced CR rates of almost 20% in the settings of both newly diagnosed and R/R AML102,103.”

What the sources say

• Not checked yetcites [102] Boutboul, D. et al. Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J. Clin. Invest. 128, 3071–3087 (2018). source
• Not checked yetcites [103] Fang, J. et al. A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes. Nat. Med. 22, 727–734 (2016). source

In the paper

“This agent has activity across a variety of MM cell lines resistant to lenalidomide and pomalidomide, even those with low levels of CRBN expression, which has been proposed as a mechanism of drug resistance (FIG. 3)120.”

What the sources say

• Not checked yetcites [120] Lonial, S. et al. First clinical (phase 1b/2a) study of iberdomide (CC-220; IBER), a CELMoD, in combination with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J. Clin. Oncol. 37, 8006–8006 (2019). source

In the paper

“Thus, altered regulation of gene expression as a result of IKZF1 degradation might also contribute to responsiveness of myeloid malignancies to lenalidomide97,101.”

What the sources say

• Not checked yetcites [97] List, A., Ebert, B. L. & Fenaux, P. A decade of progress in myelodysplastic syndrome with chromosome 5q deletion. Leukemia 32, 1493–1499 (2018). source
• Not checked yetcites [101] Sekeres, M. A. et al. A phase 2 study of lenalidomide monotherapy in patients with deletion 5q acute myeloid leukemia: Southwest Oncology Group Study S0605. Blood 118, 523–528 (2011). source

In the paper

“Avadomide has been tested in clinical trials involving patients with R/R DLBCL, demonstrating promising single-agent activity (ORR 29% and CR rate 11%)85.”

What the sources say

• Not checked yetcites [85] Vitolo, U. et al. ROBUST: first report of phase III randomized study of lenalidomide/R-CHOP (R 2 -CHOP) vs placebo/R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Hematol. Oncol. 37, 36–37 (2019). source

In the paper

“Iberdomide has also shown efficacy in models of systemic lupus erythematosus in vitro where treatment can decrease production of auto-antibodies, and trials are ongoing in this disease setting119.”

What the sources say

• Not checked yetcites [119] Sievers, Q. L. et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, eaat0572 (2018). source

In the paper

“In early phase studies, single-agent lenalidomide typically induced responses in ~30% (ORRs of 22–42%) of patients with R/R peripheral T cell lymphomas90–92, mycosis fungoides or Sézary syndrome93.”

What the sources say

• Not checked yetcites [90] Georgopoulos, K. et al. The ikaros gene is required for the development of all lymphoid lineages. Cell 79, 143–156 (1994). source
• Not checked yetcites [91] Wang, J.-H. et al. Aiolos regulates B cell activation and maturation to effector state. Immunity 9, 543–553 (1998). source
• Not checked yetcites [92] Morschhauser, F. et al. A phase 2, multicentre, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid®) in subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: the EXPECT trial. Eur. J. Cancer 49, 2869–2876 (2013). source
• Not checked yetcites [93] Ishida, T. et al. Multicenter phase II study of lenalidomide in relapsed or recurrent adult T-cell leukemia/lymphoma: ATLL-002. J. Clin. Oncol. 34, 4086–4093 (2016). source

In the paper

“This agent has promising activity in combination with dexamethasone in patients with R/R MM, with an ORR of 31% and a disease-control rate of 88%118”

What the sources say

• Not checked yetcites [118] Bjorklund, C. C. et al. Iberdomide (CC-220) is a potent cereblon E3 ligase modulator with antitumor and immunostimulatory activities in lenalidomide- and pomalidomide-resistant multiple myeloma cells with dysregulated CRBN. Leukemia 34, 1197–1201 (2019). source

In the paper

“Accordingly, mutations in TP53 lead to resistance to lenalidomide in patients with MDS97,98 (FIG. 3).”

What the sources say

• Not checked yetcites [97] List, A., Ebert, B. L. & Fenaux, P. A decade of progress in myelodysplastic syndrome with chromosome 5q deletion. Leukemia 32, 1493–1499 (2018). source
• Not checked yetcites [98] Schneider, R. K. et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell 26, 509–520 (2014). source

In the paper

“Interestingly, two other HHV8-associated neoplasms, primary effusion lymphoma111 and Castleman disease112, have also been shown to be responsive to treatment with thalidomide analogues.”

What the sources say

• Not checked yetcites [111] Chihara, D. et al. Long-term results of a phase II trial of lenalidomide plus prednisone therapy for patients with myelofibrosis. Leukemia Res. 48, 1–5 (2016). source
• Not checked yetcites [112] Bhutani, M., Polizzotto, M. N., Uldrick, T. S. & Yarchoan, R. Kaposi sarcoma–associated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment. Semin. Oncol. 42, 223–246 (2015). source

In the paper

“In mice, both Ikzf1 and Ikzf3 are required for normal T cell development and maintenance of mature T cell populations88,89”

What the sources say

• Not checked yetcites [88] Mullighan, C. G. et al. BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453, 110–114 (2008). source
• Not checked yetcites [89] Mullighan, C. G. et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N. Engl. J. Med. 360, 470–480 (2009). source

In the paper

“Lenalidomide is unlikely to have utility in patients with early B cell malignancies, such as pre-B cell acute lymphoblastic leukaemia (ALL), considering that deletions and loss of function mutations in IKZF1 promote the development of these cancers86,87.”

What the sources say

• Not checked yetcites [86] Ferreri, A. J. M. et al. Lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation: an open label, single-arm, multicentre phase 2 trial. Lancet Haematol. 4, e137–e146 (2017). source
• Not checked yetcites [87] Carpio, C. et al. Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier. Blood 135, 996–1007 (2020). source

In the paper

“CRBN expression is required for the anti-myeloma activity of lenalidomide142.”

What the sources say

• Not checked yetcites [142] Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101–114 (2016). source

In the paper

“In genome-wide genetic screens of MM cells and lymphoma cells, disruption of CRL4CRBN components and the associated cullin-RING ligase machinery was found to result in resistance to lenalidomide143–145.”

What the sources say

• Not checked yetcites [143] Burslem, G. M. & Crews, C. M. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell 181, 102–114 (2020). source
• Not checked yetcites [144] Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617 (2015). source
• Not checked yetcites [145] Zhu, Y. X. et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 118, 4771–4779 (2011). source

In the paper

“Thalidomide itself is an exception, given that it rarely causes thrombocytopenia10”

What the sources say

• Not checked yetcites [10] Rajkumar, S. V. et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J. Clin. Oncol. 24, 431–436 (2006). source

In the paper

“Furthermore, any noncatalytic, scaffolding functions of degraded proteins are also abolished, potentially broadening anti-cancer effects beyond enzymatic inhibitors that typically spare scaffolding functions (FIG. 2a).”

In the paper

“Long-term use of lenalidomide, especially following high-dose melphalan and autologous stem cell rescue, has been associated with an increased incidence of second solid tumours and haematopoietic malignancies, primarily MDS and AML34,126.”

What the sources say

• Not checked yetcites [34] Benboubker, L. et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N. Engl. J. Med. 371, 906–917 (2014). source
• Not checked yetcites [126] Mazumder, A. et al. Effect of lenalidomide therapy on mobilization of peripheral blood stem cells in previously untreated multiple myeloma patients. Leukemia 22, 1280–1281 (2007). source

In the paper

“Drugs that induce targeted protein degradation, such as thalidomide analogues, have a number of unique pharmacological features in comparison with conventional enzyme inhibitors58,138–140.”

What the sources say

• Not checked yetcites [58] Das, D. S. et al. Synergistic anti-myeloma activity of the proteasome inhibitor marizomib and the IMiD ® immunomodulatory drug pomalidomide. Br. J. Haematol. 171, 798–812 (2015). source
• Not checked yetcites [138] Lee, M. J. et al. Lenalidomide desensitization for delayed hypersensitivity reactions in 5 patients with multiple myeloma. Br. J. Haematol. 167, 127–131 (2014). source
• Not checked yetcites [139] FDA. Drugs @ FDA: FDA-approved drugs. US Food & Drug Administration https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=021880 (2019).
• Not checked yetcites [140] Pawlyn, C. et al. Lenalidomide-induced diarrhea in patients with myeloma is caused by bile acid malabsorption that responds to treatment. Blood 124, 2467–2468 (2014). source

In the paper

“Aside from neutropenia, data suggest that lenalidomide use is associated with limited immune dysfunction beyond that associated with the underlying malignancies.”

In the paper

“The increased risk seen with concomitant use of corticosteroids, such as dexamethasone, and chemotherapeutic agents, such as anthracyclines, raises the possibility of thrombosis secondary to endothelial cell injury133.”

What the sources say

• Not checked yetcites [133] Scarpace, S. et al. Arterial thrombosis in four patients treated with thalidomide. Leukemia Lymphoma 46, 239–242 (2005). source

In the paper

“Moreover, a single degrader molecule can cycle through multiple binding and degradation events, enabling sub-stoichiometric activity141.”

What the sources say

• Not checked yetcites [141] Fisher, S. L. & Phillips, A. J. Targeted protein degradation and the enzymology of degraders. Curr. Opin. Chem. Biol. 44, 47–55 (2018). source

In the paper

“Del(5q) MDS HSPCs are typically sensitive to lenalidomide-mediated depletion of CK1α, which activates p53-dependent cell death15,96.”

What the sources say

• Not checked yetcites [15] Krönke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015). source
• Not checked yetcites [96] List, A. et al. Efficacy of lenalidomide in myelodysplastic syndromes. N. Engl. J. Med. 352, 549–557 (2005). source

In the paper

“In parallel to the discovery that thalidomide analogues act as ‘molecular glue’ degraders, heterobifunctional proteolysis targeting chimeras (PROTACs), which are based on a similar principle and consist of an E3 ubiquitin ligase-recruiting element linked to a target-binding moiety, have advanced from being proof-of-concept molecules to investigational anticancer drugs (BOX 3)140.”

What the sources say

• Not checked yetcites [140] Pawlyn, C. et al. Lenalidomide-induced diarrhea in patients with myeloma is caused by bile acid malabsorption that responds to treatment. Blood 124, 2467–2468 (2014). source

In the paper

“Crystallographic and saturation mutagenesis studies have identified the amino acid residues of particular zinc finger domains that are crucial for their drug-induced recruitment to CRL4CRBN and subsequent degradation117”

What the sources say

• Not checked yetcites [117] Matyskiela, M. E. et al. A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos. J. Med. Chem. 61, 535–542 (2017). source

In the paper

“Notably, different thalidomide analogues mediate the degradation of overlapping but distinct sets of zinc finger domains117”

What the sources say

• Not checked yetcites [117] Matyskiela, M. E. et al. A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos. J. Med. Chem. 61, 535–542 (2017). source

In the paper

“implying that further chemical diversification will provide unique opportunities to target additional members of this important class of once-undruggable proteins.”

In the paper

“Two additional, entirely distinct classes of small-molecule molecular glue degraders have been discovered.”

What the sources say

• Not checked yetcites [177] Simon, G. R. et al. A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound in patients with refractory solid tumors. Cancer Chemother. Pharmacol. 68, 1233–1241 (2011). source
• Not checked yetcites [178] Rigas, J. R. et al. Phase I clinical and pharmacological study of chloroquinoxaline sulfonamide. Cancer Res. 52, 6619–6623 (1992).
• Not checked yetcites [179] Punt, C. J. A. et al. Phase I and pharmacokinetic study of E7070, a novel sulfonamide, given at a daily times five schedule in patients with solid tumors. A study by the EORTC-Early Clinical Studies Group (ECSG). Ann. Oncol. 12, 1289–1293 (2001). source
• Not checked yetcites [182] Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep. 29, 1499–1510.e6 (2019). source
• Not checked yetcites [183] Faust, T. B. et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 16, 7–14 (2020). source
• Not checked yetcites [184] Du, X. et al. Structural basis and kinetic pathway of RBM39 recruitment to DCAF15 by a sulfonamide molecular glue E7820. Structure 27, 1625–1633.e3 (2019). source

In the paper

“Each target protein has been found to contain a structural degron composed of a β-hairpin with a pinnacle glycine motif, most often in the form of a Cys2-His2 (C2H2) zinc finger domain, that binds to a composite thalidomide analogue–CRBN surface17,117,121,167.”

What the sources say

• Not checked yetcites [17] Fischer, E. S. et al. Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49–53 (2014). source
• Not checked yetcites [117] Matyskiela, M. E. et al. A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos. J. Med. Chem. 61, 535–542 (2017). source
• Not checked yetcites [121] Schafer, P. H. et al. Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus. Ann. Rheum. Dis. 77, 1516–1523 (2018). source
• Not checked yetcites [167] Zhang, B. et al. Clinical potential of mass spectrometry-based proteogenomics. Nat. Rev. Clin. Oncol. 16, 256–268 (2019). source

In the paper

“Functional genomics approaches coupled with computational docking and in vitro binding analyses have been used to interrogate all human C2H2 zinc finger domains in order to define the zinc finger ‘degrome’ of thalidomide analogues117.”

What the sources say

• Not checked yetcites [117] Matyskiela, M. E. et al. A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos. J. Med. Chem. 61, 535–542 (2017). source

In the paper

“Such analyses have revealed the importance of competition among both substrates and E3 ubiquitin ligase complexes in determining neosubstrate abundance during thalidomide analogue therapy.”

What the sources say

• Not checked yetcites [113] Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879–1888 (2018). source
• Not checked yetcites [159] Gandhi, A. K. et al. Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity. Br. J. Haematol. 164, 233–244 (2013). source

In the paper

“A number of endogenous CRBN-interacting proteins have been reported, including MEIS2, AMPK, MCT1, and GS17,170–172”

What the sources say

• Not checked yetcites [170] Petzold, G., Fischer, E. S. & Thomä, N. H. Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase. Nature 532, 127–130 (2016). source
• Not checked yetcites [171] Najafabadi, H. S. et al. C2H2 zinc finger proteins greatly expand the human regulatory lexicon. Nat. Biotechnol. 33, 555–562 (2015). source
• Not checked yetcites [172] Higgins, J. J., Pucilowska, J., Lombardi, R. Q. & Rooney, J. P. A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology 63, 1927–1931 (2004). source

In the paper

“Targeted protein degradation is influenced by multiple layers of competition for UPS components.”

In the paper

“Most known neosubstrate proteins have been identified through proteomic analyses of different cell lineages11,15,165,166.”

What the sources say

• Not checked yetcites [11] Krönke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2013). source
• Not checked yetcites [15] Krönke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015). source
• Not checked yetcites [165] Lodé, L. et al. Emergence and evolution of TP53 mutations are key features of disease progression in myelodysplastic patients with lower-risk del(5q) treated with lenalidomide. Haematologica 103, e143–e146 (2017). source
• Not checked yetcites [166] Hoofnagle, A. N., Becker, J. O., Wener, M. H. & Heinecke, J. W. Quantification of thyroglobulin, a low-abundance serum protein, by immunoaffinity peptide enrichment and tandem mass spectrometry. Clin. Chem. 54, 1796–1804 (2008). source

In the paper

“sequencing of matched clinical specimens has identified RUNX1 mutations that are associated with lenalidomide resistance97.”

What the sources say

• Not checked yetcites [97] List, A., Ebert, B. L. & Fenaux, P. A decade of progress in myelodysplastic syndrome with chromosome 5q deletion. Leukemia 32, 1493–1499 (2018). source

In the paper

“Consistent with these experimental findings, resistance to lenalidomide and disease progression are associated with an increased frequency of TP53 mutations in patients with del(5q) MDS98,161,162.”

What the sources say

• Not checked yetcites [98] Schneider, R. K. et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell 26, 509–520 (2014). source
• Not checked yetcites [161] Krönke, J. et al. IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM). Leukemia 31, 1363–1367 (2017). source
• Not checked yetcites [162] Reichermeier, K. M. et al. PIKES analysis reveals response to degraders and key regulatory mechanisms of the CRL4 network. Mol. Cell 77, 1092–1106.e9 (2020). source

In the paper

“Data from our group113 and others157 suggest that overexpression of CRBN can sensitize previously resistant MM cell lines to thalidomide analogues.”

What the sources say

• Not checked yetcites [113] Shimada, K., Hayakawa, F. & Kiyoi, H. Biology and management of primary effusion lymphoma. Blood 132, 1879–1888 (2018). source
• Not checked yetcites [157] Pourabdollah, M. et al. High IKZF1/3 protein expression is a favorable prognostic factor for survival of relapsed/refractory multiple myeloma patients treated with lenalidomide. J. Hematol. Oncol. 9, 123 (2016). source

In the paper

“Therefore, efforts to modulate CRBN expression might yield therapeutics that enhance the activity of thalidomide analogues.”

In the paper

“Accordingly, loss of p53 leads to resistance of mouse HSPCs to Ck1α targeting with either lenalidomide, a direct inhibitor or genetic knockdown (FIG. 3b)15,160.”

What the sources say

• Not checked yetcites [15] Krönke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015). source
• Not checked yetcites [160] Zhu, Y. X., Kortuem, K. M. & Stewart, A. K. Molecular mechanism of action of immune-modulatory drugs thalidomide, lenalidomide and pomalidomide in multiple myeloma. Leukemia Lymphoma 54, 683–687 (2012). source

In the paper

“More broadly, lenalidomide and the other approved thalidomide analogues provide clinical validation for the therapeutic concept of targeted protein degradation, which has increased both interest and investment in a range of related technologies.”

In the paper

“Targeted proteomic assays have been translated to the clinical laboratory setting163,164”

What the sources say

• Not checked yetcites [163] Järås, M. et al. Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia. J. Exp. Med. 211, 605–612 (2014). source
• Not checked yetcites [164] Scharenberg, C. et al. Progression in patients with low- and intermediate-1-risk del(5q) myelodysplastic syndromes is predicted by a limited subset of mutations. Haematologica 102, 498–508 (2016). source

In the paper

“Similarly, lenalidomide-mediated depletion of IKZF1 in del(5q) MDS cells drives RUNX1 upregulation and megakaryocyte differentiation”

What the sources say

• Not checked yetcites [97] List, A., Ebert, B. L. & Fenaux, P. A decade of progress in myelodysplastic syndrome with chromosome 5q deletion. Leukemia 32, 1493–1499 (2018). source

In the paper

“some of which compete with thalidomide analogue-targeted neosubstrates for CRL4CRBN-dependent ubiquitination and degradation.”

What the sources say

• Not checked yetcites [170] Petzold, G., Fischer, E. S. & Thomä, N. H. Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase. Nature 532, 127–130 (2016). source
• Not checked yetcites [171] Najafabadi, H. S. et al. C2H2 zinc finger proteins greatly expand the human regulatory lexicon. Nat. Biotechnol. 33, 555–562 (2015). source
• Not checked yetcites [172] Higgins, J. J., Pucilowska, J., Lombardi, R. Q. & Rooney, J. P. A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation. Neurology 63, 1927–1931 (2004). source

In the paper

“Beyond substrate competition for CRBN, CRBN itself competes with other substrate receptors for access to limiting concentrations of CRL4159.”

What the sources say

• Not checked yetcites [159] Gandhi, A. K. et al. Measuring cereblon as a biomarker of response or resistance to lenalidomide and pomalidomide requires use of standardized reagents and understanding of gene complexity. Br. J. Haematol. 164, 233–244 (2013). source

In the paper

“The approximately 700 C2H2 zinc finger-containing transcription factors constitute the largest class of transcription factors in the human genome168, but have previously not been amenable to drug development.”

What the sources say

• Not checked yetcites [168] Donovan, K. A. et al. Thalidomide promotes degradation of SALL4, a transcription factor implicated in duane radial ray syndrome. eLife 7, e38430 (2018). source

In the paper

“CARs fused to an additional domain allowing for PROTAC-mediated degradation have been designed as a reversible chemical safety switch203.”

What the sources say

• Not checked yetcites [203] Nabet, B. et al. Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules. Preprint at bioRxiv https://doi.org/10.1101/2020.03.13.980946 (2020). source

In the paper

“Finally, a novel cyclin K-targeting cytotoxic compound, HQ461, was identified during high-throughput screening for chemical suppressors of NRF2 activity184.”

What the sources say

• Not checked yetcites [184] Du, X. et al. Structural basis and kinetic pathway of RBM39 recruitment to DCAF15 by a sulfonamide molecular glue E7820. Structure 27, 1625–1633.e3 (2019). source

In the paper

“Cryoelectron microscopy revealed the polymerization of BCL6–BI-3802 complexes into helical filaments in vitro188.”

What the sources say

• Not checked yetcites [188] Nusse, R. & Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017). source

In the paper

“Attractive targets include oncogenic forms of β-catenin that harbor hotspot mutations in a phosphodegron sequence normally recognized by the E3 ligase SCFβ–TrCP, which result in the accumulation of β-catenin protein and thus constitutive Wnt pathway activation185.”

What the sources say

• Not checked yetcites [185] Słabicki, M. et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature 585, 293–297 (2020). source

In the paper

“The first class comprises aryl sulfonamides, including indisulam, tasisulam, E7820 and chloroquinoxaline”

What the sources say

• Not checked yetcites [173] Eichner, R. et al. Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity. Nat. Med. 22, 735–743 (2016). source
• Not checked yetcites [174] Lee, K. M. et al. Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high-fat diet-induced obesity and insulin resistance in mice. Diabetes 62, 1855–1864 (2013). source
• Not checked yetcites [175] Nguyen, T. V. et al. Glutamine triggers acetylation-dependent degradation of glutamine synthetase via the thalidomide receptor cereblon. Mol. Cell 61, 809–820 (2016). source
• Not checked yetcites [176] Mita, M. et al. Phase I study of E7820, an oral inhibitor of integrin α-2 expression with antiangiogenic properties, in patients with advanced malignancies. Clin. Cancer Res. 17, 193–200 (2011). source

In the paper

“Beyond molecular glue degraders, drug-induced polymerization is an emerging mechanism of targeted protein degradation.”

In the paper

“AP1867 and FKBP12F36V are a bump-and-hole engineered small molecule–protein pair orthogonal to rapamycin and wild-type FKBP12202.”

What the sources say

• Not checked yetcites [202] Buckley, D. L. et al. HaloPROTACS: use of small molecule protacs to induce degradation of halotag fusion proteins. ACS Chem. Biol. 10, 1831–1837 (2015). source

In the paper

“However, with the exception of newer generations of destabilization domains204, these systems are currently difficult to directly translate into clinical cellular immunotherapies because they use non-human proteins, immunosuppressive controller drugs or non-approved small molecules.”

What the sources say

• Not checked yetcites [204] Nabet, B. et al. The dTAG system for immediate and target-specific protein degradation. Nat. Chem. Biol. 14, 431–441 (2018). source

In the paper

“Thus, selective complementarity between the surfaces of DDB1 and CDK12 hold promise for the future development of cyclin K degrader therapeutics182.”

What the sources say

• Not checked yetcites [182] Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep. 29, 1499–1510.e6 (2019). source

In the paper

“Two independent groups identified RNA-binding motif protein 39 (RBM39, also known as CAPERα), a nuclear protein involved in pre-mRNA splicing, as the direct molecular target responsible for the antitumour effect of these sulfonamides, which recruit this splicing factor to the CRL4DCAF15 E3 ubiquitin ligase for polyubiquitination and subsequent proteasomal degradation177–179.”

What the sources say

• Not checked yetcites [177] Simon, G. R. et al. A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound in patients with refractory solid tumors. Cancer Chemother. Pharmacol. 68, 1233–1241 (2011). source
• Not checked yetcites [178] Rigas, J. R. et al. Phase I clinical and pharmacological study of chloroquinoxaline sulfonamide. Cancer Res. 52, 6619–6623 (1992).
• Not checked yetcites [179] Punt, C. J. A. et al. Phase I and pharmacokinetic study of E7070, a novel sulfonamide, given at a daily times five schedule in patients with solid tumors. A study by the EORTC-Early Clinical Studies Group (ECSG). Ann. Oncol. 12, 1289–1293 (2001). source

In the paper

“Kinetic and structural analyses revealed relatively weak drug–protein interactions that are stabilized by ternary docking across broad protein–protein interfaces, which results in highly selective drug-dependent protein degradation of RBM39 and its paralogue RBM23179–181.”

What the sources say

• Not checked yetcites [179] Punt, C. J. A. et al. Phase I and pharmacokinetic study of E7070, a novel sulfonamide, given at a daily times five schedule in patients with solid tumors. A study by the EORTC-Early Clinical Studies Group (ECSG). Ann. Oncol. 12, 1289–1293 (2001). source
• Not checked yetcites [180] Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, eaal3755 (2017). source
• Not checked yetcites [181] Uehara, T. et al. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat. Chem. Biol. 13, 675–680 (2017). source

In the paper

“With regard to the second novel class of agents, three independent chemogenomic screening studies resulted in the identification of structurally diverse molecular glue degraders of cyclin K.”

What the sources say

• Not checked yetcites [182] Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep. 29, 1499–1510.e6 (2019). source
• Not checked yetcites [183] Faust, T. B. et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 16, 7–14 (2020). source
• Not checked yetcites [184] Du, X. et al. Structural basis and kinetic pathway of RBM39 recruitment to DCAF15 by a sulfonamide molecular glue E7820. Structure 27, 1625–1633.e3 (2019). source

In the paper

“Drug-induced polymerization promoted BCL6 degradation by the E3 ubiquitin ligase SIAH1, which recognizes a linear degron sequence distal to the drug-binding domain188.”

What the sources say

• Not checked yetcites [188] Nusse, R. & Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017). source

In the paper

“A molecular switch consisting of a thalidomide analogue and a variable protein construct with a human zinc finger degron tag would probably be suitable for clinical use.”

In the paper

“Accordingly, AP1867-derivative PROTACs can mediate the selective degradation of heterologous FKBP12F36V-tagged proteins, enforcing rapid and potent depletion in vitro and in vivo200,201.”

What the sources say

• Not checked yetcites [200] Chung, H. K. et al. Tunable and reversible drug control of protein production via a self-excising degron. Nat. Chem. Biol. 11, 713–720 (2015). source
• Not checked yetcites [201] Neklesa, T. K. et al. Small-molecule hydrophobic tagging–induced degradation of HaloTag fusion proteins. Nat. Chem. Biol. 7, 538–543 (2011). source

In the paper

“which to date have produced modest response rates as monotherapy in clinical trials involving patients with advanced-stage solid tumours173–176.”

What the sources say

• Not checked yetcites [173] Eichner, R. et al. Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity. Nat. Med. 22, 735–743 (2016). source
• Not checked yetcites [174] Lee, K. M. et al. Disruption of the cereblon gene enhances hepatic AMPK activity and prevents high-fat diet-induced obesity and insulin resistance in mice. Diabetes 62, 1855–1864 (2013). source
• Not checked yetcites [175] Nguyen, T. V. et al. Glutamine triggers acetylation-dependent degradation of glutamine synthetase via the thalidomide receptor cereblon. Mol. Cell 61, 809–820 (2016). source
• Not checked yetcites [176] Mita, M. et al. Phase I study of E7820, an oral inhibitor of integrin α-2 expression with antiangiogenic properties, in patients with advanced malignancies. Clin. Cancer Res. 17, 193–200 (2011). source

In the paper

“In addition, Nabet and colleagues200,201 have developed the dTag system that uses PROTACs composed of a CRBN or VHL ligand, a linker and an AP1867 derivative.”

What the sources say

• Not checked yetcites [200] Chung, H. K. et al. Tunable and reversible drug control of protein production via a self-excising degron. Nat. Chem. Biol. 11, 713–720 (2015). source
• Not checked yetcites [201] Neklesa, T. K. et al. Small-molecule hydrophobic tagging–induced degradation of HaloTag fusion proteins. Nat. Chem. Biol. 7, 538–543 (2011). source

In the paper

“To further develop this concept, ‘super-degron’ tags composed of hybrid zinc finger degrons have been engineered to enhance the efficiency of drug-mediated degradation117,207.”

What the sources say

• Not checked yetcites [117] Matyskiela, M. E. et al. A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos. J. Med. Chem. 61, 535–542 (2017). source
• Not checked yetcites [207] Weber, E. W. et al. Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells. Preprint at bioRxiv https://doi.org/10.1101/2020.01.26.920496 (2020). source

In the paper

“Two decades of development have culminated in the clinical testing of the first of many small-molecule PROTAC drugs, ARV-110 (NCT03888612).”

What the sources say

• Not checked yetcites NCT03888612

In the paper

“These super-degron tags have been incorporated into thalidomide analogue-mediated off-switch CARs, which can be degraded and thus functionally inhibited at sub-therapeutic drug concentrations (FIG. 4)207.”

What the sources say

• Not checked yetcites [207] Weber, E. W. et al. Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells. Preprint at bioRxiv https://doi.org/10.1101/2020.01.26.920496 (2020). source