Immunomodulatory agents lenalidomide and pomalidomide co‐stimulate T cells by inducing degradation of T cell repressors I karos and A iolos via modulation of the E 3 ubiquitin ligase complex CRL 4 CRBN
Open accessAbstract
Summary: Cereblon ( CRBN ), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E 3 ubiquitin ligase complex, CRL 4 CRBN . T cell co‐stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL 4 CRBN substrates responsible for T cell co‐stimulation have yet to be identified. Here we demonstrate that interaction of the transcription factors Ikaros ( IKZF 1, encoded by the IKZF 1 gene) and A iolos ( IKZF 3, encoded by the IKZF 3 gene) with CRL 4 CRBN is induced by lenalidomide or pomalidomide. Each agent promotes A iolos and I karos binding to CRL 4 CRBN with enhanced ubiquitination leading to cereblon‐dependent proteosomal degradation in T lymphocytes. We confirm that A iolos and I karos are transcriptional repressors of interleukin‐2 expression. The findings link lenalidomide‐ or pomalidomide‐induced degradation of these transcriptional suppressors to well documented T cell activation. Importantly, Aiolos could serve as a proximal pharmacodynamic marker for lenalidomide and pomalidomide, as healthy human subjects administered lenalidomide demonstrated A iolos degradation in their peripheral T cells. In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of I karos and A iolos to CRL 4 CRBN , leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In 2014, landmark studies revealed that thalidomide and lenalidomide did not behave as inhibitors but functioned as molecular glue degraders analogous to auxin degrader TIR1.
“the second breakthrough came in 2014 when a series of landmark studies revealed that thalidomide, and its more potent derivative lenalidomide, did not behave as inhibitors but in fact functioned as molecular glue degraders analogous to the auxin degrader tiR1 (chamberlain et al. 2014;Fischer et al. 2014;gandhi et al. 2014;Krönke et al. 2014;lu et al. 2014).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Gandhi et al. 2014
The Discussion (page unavailable) reports that lenalidomide promotes CRL4CRBN-mediated recruitment and degradation of Ikaros and Aiolos, rather than simply inhibiting the ligase. The paper studies lenalidomide and pomalidomide, not thalidomide as a degrader, and the cited passages do not establish an analogy to auxin–TIR1. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFollowing iMiD treatment and selective degradation of IKZF1, T cells increase production of IFN-γ, IL-21, and IL-2, enhancing the anti-tumor capability of the immune system.
“Following iMiD treatment and the selective degradation of iKZF1, t cells increase their production of iFN-γ, il-21, and il-2 enhancing the anti-tumor capability of the immune system to target the cancerous plasma cells (gandhi et al. 2014;D'Souza et al. 2021;Bird and Pawlyn 2023) (Figure 5A, iii).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as gandhi et al. 2014
The Results section on Ikaros knockdown reports increased IL-2 production in T cells, and the Discussion identifies IFN-γ among cytokines negatively regulated by Ikaros. But the paper describes drug-induced degradation of both IKZF1 (Ikaros) and IKZF3 (Aiolos), not IKZF1 alone. Our copy does not report increased IL-21 or show that these cytokine changes enhance targeting of cancerous plasma cells. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLenalidomide promotes the interaction between CRBN and IKZF1 and IKZF3.
“lenalidomide was shown to promote the interaction between cRBN and two members of the ikaros transcription factor family: iKZF1 and iKZF3 (gandhi et al. 2014;Krönke et al. 2014;lu et al. 2014).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Gandhi et al. 2014
MG degraders can induce the degradation of target proteins otherwise deemed unligandable, such as IKZF1/3 and RBM39.
“(ii) can induce the degradation of target proteins otherwise deemed unligandable (e.g., IKZF1/3, RBM39); [44][45][46][47][48][49][50][51][52][53][54][55]”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [46]
IMiDs trigger CRBN-dependent proteasomal degradation of the transcription factors IKZF1 and IKZF3.
“In brief, IMiDs were first shown to trigger CRBN-dependent proteasomal degradation of the C2H2-type zing-finger transcription factors Ikaros (IKZF1) and Aiolos (IKZF3).[46][47][48]”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [46]
IMiD binding to the E3 CRL4 CRBN leads to induced degradation of several targets.
“Seminal biochemical and structural studies uncovered that IMiD binding to the E3 CRL4 CRBN leads to the induced degradation of several targets.[44][45][46][47][48][49][50]”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [46]
Lenalidomide and pomalidomide induce CRBN-dependent ubiquitination and degradation of Ikaros and Aiolos, transcription factors required for development of lymphoids and survival of multiple myeloma.
“lenalidomide and pomalidomide induce CRBN-dependent ubiquitination and degradation of Ikaros and Aiolos, transcription factors required for the development of lymphoids and survival of multiple myeloma8–10.”
From Genome-wide screening reveals a role for subcellular localization of CRBN in the anti-myeloma activity of pomalidomide (2020) · cites this paper as [10]
Thalidomide analogues co-opt CRBN to target IKAROS family zinc finger 1 (IKZF1) and IKZF3 for degradation, and are now considered as pioneering examples of molecular glues.
“These drugs co-opt CRBN to target IKAROS family zinc finger 1 (IKZF1) and IKZF3 for degradation3,4,24, and are now considered as pioneering examples of molecular glues.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [24]
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 proteasomal degradation.
“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.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [13]
Thalidomide and its analogues do not inhibit the enzymatic activity of CRL4CRBN, but instead confer neomorphic activity on CRBN to mediate selective ubiquitination and proteasomal degradation of IKZF1 and IKZF3 in MM cells and T cells.
“thalidomide and its analogues do not inhibit the enzymatic activity of CRL4CRBN, but instead confer neomorphic activity on CRBN to mediate the selective ubiquitination and resultant proteasomal degradation of the transcription factors Ikaros family zinc finger protein 1 (IKZF1) and IKZF3 (Aiolos) in MM cells and T cells11–13.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [13]
In T cells, the ubiquitination and degradation of Ikaros and Aiolos induced by IMiDs leads to enhanced expression of IL-2.
“our group, in collaboration with Celgene, demonstrated that in T cells, the ubiquitination and degradation of Ikaros and Aiolos induced by IMiDs leads to the enhanced expression of IL-2 [27].”
From Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs (2016) · cites this paper as [27]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829 · see citing works
Identification of a Primary Target of Thalidomide Teratogenicity
Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y., & Handa, H. (2010) · Science · doi:10.1126/science.1177319 · Cited by 2,136 · see citing works
Self-citationSystematic and Quantitative Assessment of the Ubiquitin-Modified Proteome
Kim, W., Bennett, E. J., Huttlin, E. L., Guo, A., Li, J., Possemato, A. P., Sowa, M. E., Rad, R., Rush, A. J., Comb, M. J., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.025 · Cited by 1,582 · see citing works
Lopez-Girona, A., Mendy, D., Ito, T., Miller, K., Gandhi, A. K., Kang, J., Karasawa, S., Carmel, G., Jackson, P., Abbasian, M., et al. (2012) · Leukemia · doi:10.1038/leu.2012.119 · Cited by 814 · see citing works
Self-citationCorral, L. G., Haslett, P. A. J., Muller, G. W., Chen, R., Wong, L. M., Ocampo, C. J., Patterson, R. T., Stirling, D., & Kaplan, G. (1999) · PubMed · Cited by 729 · see citing works
Corral, L. G., Haslett, P. A. J., Muller, G. W., Chen, R., Wong, L.-M., Ocampo, C. J., Patterson, R. T., Stirling, D., & Kaplan, G. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.1.380 · Cited by 654 · see citing works
Wang, J., Nichogiannopoulou, A., Wu, L. J., Sun, L., Sharpe, A. H., Bigby, M. E., & Georgopoulos, K. (1996) · Immunity · doi:10.1016/s1074-7613(00)80269-1 · Cited by 614 · see citing works
Self-citationCereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide
Zhu, Y. X., Braggio, E., Shi, C.-X., Bruins, L. A., Schmidt, J. E., Van Wier, S., Chang, X.-B., Bjorklund, C. C., Fonseca, R., Bergsagel, P. L., et al. (2011) · Blood · doi:10.1182/blood-2011-05-356063 · Cited by 607 · see citing works
Ramsay, A. G., Johnson, A. J., Lee, A. M., Görgün, G., Dieu, R. L., Blum, W. G., Byrd, J. C., & Gribben, J. G. (2008) · Journal of Clinical Investigation · doi:10.1172/jci35017 · Cited by 604 · see citing works
Ikaros DNA-Binding Proteins Direct Formation of Chromatin Remodeling Complexes in Lymphocytes
Kim, J., Sif, S., Jones, B., Jackson, A., Koipally, J., Heller, E., Winandy, S., Viel, A., Sawyer, A., Ikeda, T., et al. (1999) · Immunity · doi:10.1016/s1074-7613(00)80034-5 · Cited by 587 · see citing works
Gandhi, R., Kumar, D., Burns, E. J., Nadeau, M., Dake, B., Laroni, A., Kozoriz, D., Weiner, H. L., & Quintana, F. J. (2010) · Nature Immunology · doi:10.1038/ni.1915 · Cited by 476 · see citing works
Wu, L., Adams, M., Carter, T., Chen, R., Muller, G. W., Stirling, D., Schafer, P. H., & Bartlett, J. B. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-4405 · Cited by 439 · see citing works
Self-citationGalustian, C., Meyer, B., Labarthe, M., Dredge, K. S., Klaschka, D., Henry, J. Y., Todryk, S. M., Chen, R., Muller, G. W., Stirling, D., et al. (2008) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-008-0620-4 · Cited by 389 · see citing works
Self-citationAiolos Regulates B Cell Activation and Maturation to Effector State
Wang, J.-H., Avitahl, N., Cariappa, A., Friedrich, C., Ikeda, T., Renold, A., Andrikopoulos, K., Liang, L., Pillai, S., Morgan, B. A., et al. (1998) · Immunity · doi:10.1016/s1074-7613(00)80637-8 · Cited by 321 · see citing works
Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes
Koipally, J., Renold, A., Kim, J., & Georgopoulos, K. (1999) · The EMBO Journal · doi:10.1093/emboj/18.11.3090 · Cited by 304 · see citing works
Aiolos promotes TH17 differentiation by directly silencing Il2 expression
Quintana, F. J., Jin, H., Burns, E. J., Nadeau, M., Yeste, A., Kumar, D., Rangachari, M., Zhu, C. Y., Xiao, S., Seavitt, J., et al. (2012) · Nature Immunology · doi:10.1038/ni.2363 · Cited by 250 · see citing works
Chen, N., Lau, H. S. H., Kong, L., Kumar, G. N., Zeldis, J. B., Knight, R., & Laskin, O. L. (2007) · The Journal of Clinical Pharmacology · doi:10.1177/0091270007309563 · Cited by 248 · see citing works
Thompson, E. C., Cobb, B. S., Sabbattini, P. M. R., Meixlsperger, S., Parelho, V., Liberg, D., Taylor, B., Dillon, N., Georgopoulos, K., Jumaa, H., et al. (2007) · Immunity · doi:10.1016/j.immuni.2007.02.010 · Cited by 203 · see citing works
Schafer, P. H., Gandhi, A. K., Loveland, M. A., Chen, R. S., Man, H., Schnetkamp, P. P. M., Wolbring, G., Govinda, S., Corral, L. G., Payvandi, F., et al. (2003) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.102.048496 · Cited by 182 · see citing works
Self-citationDredge, K. S., Marriott, J. B., Todryk, S. M., Muller, G. W., Chen, R., Stirling, D., & Dalgleish, A. G. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.10.4914 · Cited by 163 · see citing works
Ikaros and Aiolos Inhibit Pre-B-Cell Proliferation by Directly Suppressing c-Myc Expression
Ma, S., Pathak, S., Mandal, M., Trinh, L., Clark, M. R., & Lu, R. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00224-10 · Cited by 138 · see citing works
Ferreirós-Vidal, I., Carroll, T., Taylor, B., Terry, A. V., Liang, Z., Bruno, L., Dharmalingam, G., Khadayate, S. P., Cobb, B. S., Smale, S. T., et al. (2013) · Blood · doi:10.1182/blood-2012-08-450114 · Cited by 121 · see citing works
Expression of Aberrantly Spliced Oncogenic Ikaros Isoforms in Childhood Acute Lymphoblastic Leukemia
Sun, L., Goodman, P. A., Wood, C. M., et al. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.12.3753 · Cited by 118 · see citing works
Iacobucci, I., Lonetti, A., Messa, F., et al. (2008) · Blood · doi:10.1182/blood-2007-09-112631 · Cited by 109 · see citing works
Bandyopadhyay, S., Duré, M., Paroder, M., Soto-Nieves, N., Puga, I., & Macián, F. (2007) · Blood · doi:10.1182/blood-2006-07-037754 · Cited by 104 · see citing works
Thomas, R. M., Chunder, N., Chen, C., Umetsu, S. E., Winandy, S., & Wells, A. D. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.11.7305 · Cited by 91 · see citing works
Helios Deficiency Has Minimal Impact on T Cell Development and function
Cai, Q., Dierich, A., Oulad‐Abdelghani, M., Chan, S. H., & Kastner, P. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901407 · Cited by 79 · see citing works
Integrative genomic analyses on Ikaros and its expression related to solid cancer prognosis
Yang, Y. (2010) · Oncology Reports · doi:10.3892/or_00000894 · Cited by 35 · see citing works
Gandhi, A. K., Shi, T., Li, M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0080437 · Cited by 31 · see citing works
Self-citationNückel, H., Frey, U. H., Sellmann, L., Collins, C. H., Dührsen, U., & Siffert, W. (2008) · British Journal of Haematology · doi:10.1111/j.1365-2141.2008.07442.x · Cited by 31 · see citing works
Differential aiolos expression in human hematopoietic subpopulations
Billot, K., Parizot, C., Arrouss, I., Mazier, D., Debré, P., Rogner, U. C., & Rebollo, A. (2009) · Leukemia Research · doi:10.1016/j.leukres.2009.05.016 · Cited by 24 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
PROTAC targeted protein degraders: the past is prologue
Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395 · see citing works
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486 · see citing works
Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide
Fischer, E. S., Böhm, K., Lydeard, J. R., Yang, H., Stadler, M. B., Cavadini, S., Nagel, J., Serluca, F., Acker, V., Lingaraju, G. M., et al. (2014) · Nature · doi:10.1038/nature13527 · Cited by 1,141 · see citing works
Proteasome inhibitors in cancer therapy
Manasanch, E. E., & Orlowski, R. Z. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.206 · Cited by 1,024 · see citing works
Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960 · see citing works
Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS
Krönke, J., Fink, E. C., Hollenbach, P. W., MacBeth, K. J., Hurst, S. N., Udeshi, N. D., Chamberlain, P. P., Mani, D. R., Man, H. W., Gandhi, A. K., et al. (2015) · Nature · doi:10.1038/nature14610 · Cited by 863 · see citing works
Self-citationA novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase
Matyskiela, M. E., Lu, G., Ito, T., Pagarigan, B., Lu, C.-C., Miller, K., Fang, W., Wang, N.-Y., Nguyen, D., Houston, J., et al. (2016) · Nature · doi:10.1038/nature18611 · Cited by 701 · see citing works
Self-citationStructural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase
Petzold, G., Fischer, E. S., & Thomä, N. H. (2016) · Nature · doi:10.1038/nature16979 · Cited by 620 · see citing works
Plasticity in binding confers selectivity in ligand-induced protein degradation
Nowak, R. P., DeAngelo, S. L., Buckley, D., He, Z., Donovan, K. A., An, J., Safaee, N., Jedrychowski, M. P., Ponthier, C. M., Ishoey, M., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0055-y · Cited by 615 · see citing works
Donovan, K. A., An, J., Nowak, R. P., Yuan, J. C., Fink, E. C., Berry, B. C., Ebert, B. L., & Fischer, E. S. (2018) · eLife · doi:10.7554/elife.38430 · Cited by 509 · see citing works
Chamberlain, P. P., Lopez-Girona, A., Miller, K., Carmel, G., Pagarigan, B., Chie-Leon, B., Rychak, E., Corral, L. G., Ren, Y. J., Wang, M., et al. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2874 · Cited by 531 · see citing works
Self-citationDevelopment of targeted protein degradation therapeutics
Chamberlain, P. P., & Hamann, L. G. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0362-y · Cited by 489 · see citing works
Leonard, J. P., Trneny, M., Izutsu, K., Fowler, N. H., Hong, X., Zhu, J., Zhang, H., Offner, F., Scheliga, A., Nowakowski, G. S., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.19.00010 · Cited by 434 · see citing works
Rational discovery of molecular glue degraders via scalable chemical profiling
Mayor-Ruiz, C., Bauer, S., Brand, M., Kozicka, Z., Siklos, M., Imrichova, H., Kaltheuner, I. H., Hahn, E., Seiler, K., Koren, A., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0594-x · Cited by 369 · see citing works
Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma
Morschhauser, F., Fowler, N. H., Feugier, P., Bouabdallah, R., Tilly, H., Palomba, M. L., Fruchart, C., Libby, E. N., Casasnovas, R.-O., Flinn, I. W., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1805104 · Cited by 373 · see citing works
Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery
Dong, G., Ding, Y., He, S., & Sheng, C. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00895 · Cited by 369 · see citing works
SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate
Matyskiela, M. E., Couto, S., Zheng, X., Lu, G., Hui, J., Stamp, K., Drew, C., Ren, Y., Wang, M., Carpenter, A., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0129-x · Cited by 338 · see citing works
Mechanisms of action of lenalidomide in B-cell non-Hodgkin lymphoma
Gribben, J. G., Fowler, N., & Morschhauser, F. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.5363 · Cited by 296 · see citing works
A Cereblon Modulator (CC-220) with Improved Degradation of Ikaros and Aiolos
Matyskiela, M. E., Zhang, W., Man, H.-W., Muller, G., Khambatta, G., Baculi, F., Hickman, M., LeBrun, L., Pagarigan, B., Carmel, G., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01921 · Cited by 309 · see citing works
Self-citationHomolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML
Brand, M., Jiang, B., Bauer, S., Donovan, K. A., Liang, Y., Wang, E. S., Nowak, R. P., Yuan, J. C., Zhang, T., Kwiatkowski, N., et al. (2019) · Cell Chemical Biology · doi:10.1016/j.chembiol.2018.11.006 · Cited by 258 · see citing works
Hansen, J. D., Correa, M., Nagy, M. A., Alexander, M., Plantevin, V., Grant, V., Whitefield, B., Huang, D., Kercher, T., Harris, R., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01928 · Cited by 240 · see citing works
Self-citationSurka, C., Jin, L., Mbong, N., Lu, C.-C., Jang, I. S., Rychak, E., Mendy, D., Clayton, T., Tindall, E., Hsu, C., et al. (2021) · Blood · doi:10.1182/blood.2020008676 · Cited by 229 · see citing works
Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15
Faust, T. B., Yoon, H., Nowak, R. P., Donovan, K. A., Li, Z., Cai, Q., Eleuteri, N. A., Zhang, T., Gray, N. S., & Fischer, E. S. (2020) · Nature Chemical Biology · doi:10.1038/s41589-019-0378-3 · Cited by 218 · see citing works
Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction
Simonetta, K. R., Taygerly, J., Boyle, K., Basham, S. E., Padovani, C., Lou, Y., Cummins, T. J., Yung, S. L., von Soly, S. K., Kayser, F., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09358-9 · Cited by 217 · see citing works
The novel mechanism of lenalidomide activity
Fink, E. C., & Ebert, B. L. (2015) · Blood · doi:10.1182/blood-2015-07-567958 · Cited by 213 · see citing works
Targeted Protein Degradation by Small Molecules
Bondeson, D. P., & Crews, C. M. (2017) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103507 · Cited by 207 · see citing works
Hagner, P. R., Man, H.-W., Fontanillo, C., Wang, M., Couto, S., Breider, M., Bjorklund, C., Havens, C. G., Lu, G., Rychak, E., et al. (2015) · Blood · doi:10.1182/blood-2015-02-628669 · Cited by 203 · see citing works
Self-citationChasing molecular glue degraders: screening approaches
Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C., & Mayor-Ruiz, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00197g · Cited by 200 · see citing works
pSILAC mass spectrometry reveals ZFP91 as IMiD-dependent substrate of the CRL4CRBN ubiquitin ligase
An, J., Ponthier, C. M., Sack, R., Seebacher, J., Stadler, M. B., Donovan, K. A., & Fischer, E. S. (2017) · Nature Communications · doi:10.1038/ncomms15398 · Cited by 176 · see citing works
Eichner, R., Heider, M., Fernández-Sáiz, V., van Bebber, F., Garz, A.-K., Lemeer, S., Rudelius, M., Targosz, B.-S., Jacobs, L., Knorn, A.-M., et al. (2016) · Nature Medicine · doi:10.1038/nm.4128 · Cited by 183 · see citing works
Harnessing the Power of Proteolysis for Targeted Protein Inactivation
Verma, R., Mohl, D., & Deshaies, R. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.010 · Cited by 185 · see citing works
From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation
Oleinikovas, V., Gainza, P., Ryckmans, T., Fasching, B., & Thomä, N. H. (2024) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-022123-104147 · Cited by 178 · see citing works
Haven't got a glue: Protein surface variation for the design of molecular glue degraders
Kozicka, Z., & Thomä, N. H. (2021) · Cell Chemical Biology · doi:10.1016/j.chembiol.2021.04.009 · Cited by 170 · see citing works
Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide
Jan, M., Sperling, A. S., & Ebert, B. L. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00479-z · Cited by 137 · see citing works
Crbn I391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice
Fink, E. C., McConkey, M., Adams, D. N., Haldar, S. D., Kennedy, J. A., Guirguis, A. A., Udeshi, N. D., Mani, D. R., Chen, M., Liddicoat, B., et al. (2018) · Blood · doi:10.1182/blood-2018-05-852798 · Cited by 131 · see citing works
Targeted protein degradation and the enzymology of degraders
Fisher, S. L., & Phillips, A. J. (2018) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2018.05.004 · Cited by 126 · see citing works
Sievers, Q. L., Gasser, J. A., Cowley, G. S., Fischer, E. S., & Ebert, B. L. (2018) · Blood · doi:10.1182/blood-2018-01-821769 · Cited by 124 · see citing works
Acute pharmacological degradation of Helios destabilizes regulatory T cells
Wang, E. S., Verano, A. L., Nowak, R. P., Yuan, J. C., Donovan, K. A., Eleuteri, N. A., Yue, H., Ngo, K. H., Lizotte, P. H., Gokhale, P. C., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00802-w · Cited by 124 · see citing works
Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex
Matyskiela, M. E., Clayton, T., Zheng, X., Mayne, C., Tran, E., Carpenter, A., Pagarigan, B., McDonald, J., Rolfe, M., Hamann, L. G., et al. (2020) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-0405-9 · Cited by 103 · see citing works
Cereblon modulators: Low molecular weight inducers of protein degradation
Chamberlain, P. P., & Cathers, B. E. (2019) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2019.02.004 · Cited by 106 · see citing works
Rocca, Y. S., Roberti, M. P., Juliá, E. P., Pampena, M. B., Bruno, L., Rivero, S., Huertas, E., Sánchez Loria, F., Pairola, A., Caignard, A., et al. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00413 · Cited by 97 · see citing works
Mining the CRBN target space redefines rules for molecular glue-induced neosubstrate recognition
Petzold, G., Gainza, P., Annunziato, S., Lamberto, I., Trenh, P., McAllister, L. A., DeMarco, B., Schwander, L., Bunker, R. D., Zlotosch, M., et al. (2025) · Science · doi:10.1126/science.adt6736 · Cited by 117 · see citing works
Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide
Furihata, H., Yamanaka, S., Honda, T., Miyauchi, Y., Asano, A., Shibata, N., Tanokura, M., Sawasaki, T., & Miyakawa, T. (2020) · Nature Communications · doi:10.1038/s41467-020-18488-4 · Cited by 89 · see citing works
p97/VCP promotes degradation of CRBN substrate glutamine synthetase and neosubstrates
Nguyen, T. V., Li, J., Lu, C.-C. (., Mamrosh, J. L., Lu, G., Cathers, B. E., & Deshaies, R. J. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1700949114 · Cited by 85 · see citing works
Cereblon and its downstream substrates as molecular targets of immunomodulatory drugs
Ito, T., & Handa, H. (2016) · International Journal of Hematology · doi:10.1007/s12185-016-2073-4 · Cited by 84 · see citing works
Self-citationFang, J., Liu, X., Bolanos, L., Barker, B., Rigolino, C., Cortelezzi, A., Oliva, E. N., Cuzzola, M., Grimes, H. L., Fontanillo, C., et al. (2016) · Nature Medicine · doi:10.1038/nm.4127 · Cited by 83 · see citing works
Thalidomide mimics uridine binding to an aromatic cage in cereblon
Hartmann, M. D., Boichenko, I., Coles, M., Zanini, F., Lupas, A. N., & Hernandez Alvarez, B. (2014) · Journal of Structural Biology · doi:10.1016/j.jsb.2014.10.010 · Cited by 83 · see citing works
UBE2G1 governs the destruction of cereblon neomorphic substrates
Lu, G., Weng, S., Matyskiela, M., Zheng, X., Fang, W., Wood, S., Surka, C., Mizukoshi, R., Lu, C.-C., Mendy, D., et al. (2018) · eLife · doi:10.7554/elife.40958 · Cited by 78 · see citing works
Schafer, P. H., Ye, Y., Wu, L., Kosek, J., Ringheim, G., Yang, Z., Liu, L., Thomas, M., Palmisano, M., & Chopra, R. (2018) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2017-212916 · Cited by 78 · see citing works
Self-citationPIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network
Reichermeier, K. M., Straube, R., Reitsma, J. M., Sweredoski, M. J., Rose, C. M., Moradian, A., den Besten, W., Hinkle, T., Verschueren, E., Petzold, G., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2019.12.013 · Cited by 78 · see citing works
Carpio, C., Bouabdallah, R., Ysebaert, L., Sancho, J.-M., Salles, G., Cordoba, R., Pinto, A., Gharibo, M., Rasco, D., Panizo, C., et al. (2020) · Blood · doi:10.1182/blood.2019002395 · Cited by 72 · see citing works
Self-citationProfiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders
Gosavi, P. M., Ngan, K. C., Yeo, M. J. R., Su, C., Li, J., Lue, N. Z., Hoenig, S. M., & Liau, B. B. (2022) · ACS Central Science · doi:10.1021/acscentsci.1c01603 · Cited by 56 · see citing works
A critical evaluation of the approaches to targeted protein degradation for drug discovery
Chopra, R., Sadok, A., & Collins, I. (2019) · Drug Discovery Today: Technologies · doi:10.1016/j.ddtec.2019.02.002 · Cited by 53 · see citing works
Self-citationA decade of progress in myelodysplastic syndrome with chromosome 5q deletion
List, A., Ebert, B. L., & Fenaux, P. (2018) · Leukemia · doi:10.1038/s41375-018-0029-9 · Cited by 49 · see citing works
Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders
Kroupova, A., Spiteri, V. A., Rutter, Z. J., Furihata, H., Darren, D., Ramachandran, S., Chakraborti, S., Haubrich, K., Pethe, J., Gonzales, D., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52871-9 · Cited by 47 · see citing works
Krönke, J., Kuchenbauer, F., Kull, M., Teleanu, V, Bullinger, L., Bunjes, D., Greiner, A., Kolmus, S., Köpff, S., Schreder, M., et al. (2017) · Leukemia · doi:10.1038/leu.2016.384 · Cited by 46 · see citing works
Shen, C., Nayak, A., Neitzel, L. R., Adams, A. A., Silver-Isenstadt, M., Sawyer, L. M., Benchabane, H., Wang, H., Bunnag, N., Li, B., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25634-z · Cited by 43 · see citing works
Targeting oncoproteins with a positive selection assay for protein degraders
Koduri, V., Duplaquet, L., Lampson, B. L., Wang, A. C., Sabet, A. H., Ishoey, M., Paulk, J., Teng, M., Harris, I. S., Endress, J. E., et al. (2021) · Science Advances · doi:10.1126/sciadv.abd6263 · Cited by 44 · see citing works
Tateno, S., Iida, M., Fujii, S., Suwa, T., Katayama, M., Tokuyama, H., Yamamoto, J., Ito, T., Sakamoto, S., Handa, H., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-61027-w · Cited by 36 · see citing works
Self-citationMolecular glue degraders: exciting opportunities for novel drug discovery
Lemaitre, T., Cornu, M., Schwalen, F., Since, M., Kieffer, C., & Voisin-Chiret, A. S. (2024) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2024.2306845 · Cited by 36 · see citing works
Jonasova, A., Bokorova, R., Polak, J., Vostry, M., Kostecka, A., Hajkova, H., Neuwirtova, R., Siskova, M., Sponerova, D., Cermak, J., et al. (2015) · European Journal of Haematology · doi:10.1111/ejh.12457 · Cited by 31 · see citing works
Structural Dynamics of the Cereblon Ligand Binding Domain
Hartmann, M. D., Boichenko, I., Coles, M., Lupas, A. N., & Hernandez Alvarez, B. (2015) · PLOS ONE · doi:10.1371/journal.pone.0128342 · Cited by 31 · see citing works
Patil, A., Manzano, M., & Gottwein, E. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019031732 · Cited by 29 · see citing works
From serendipity to strategy: molecular glue degraders in cancer therapeutics
Darling, S., Bajrami, I., & West, S. C. (2025) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2025.2564068 · Cited by 10 · see citing works
Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry
Annunziato, S., Quan, C., Donckele, E. J., Lamberto, I., Bunker, R. D., Zlotosch, M., Schwander, L., Murthy, A., Wiedmer, L., Staehly, C., et al. (2026) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01738-8 · Cited by 9 · see citing works
- Authors
- Gandhi, A. K., Kang, J., Havens, C. G., Conklin, T., Ning, Y., Wu, L., Ito, T., Ando, H., Waldman, M. F., Thakurta, A., Klippel, A., Handa, H., Daniel, T. O., Schafer, P. H., & Chopra, R.
- Affiliations
- Celgene (United States) (US)
- Celgene Corporation San Diego CA USA
- Tokyo Medical University (JP)
- Corresponding author
- Gandhi, Anita K.
- ORCID
- Venue
- British Journal of Haematology
- Publisher
- Wiley
- Published
- 2013-12-13
- Volume
- 164
- Issue
- 6
- Pages
- 811-821
- ISSN
- 0007-1048 (ISSN-L)
- 1365-2141
- PMC
- PMC4232904
- OpenAlex
- W1973999018
- Cited by
- 619
- References
- 31
- Citations by year
- 2026: 24 · 2025: 57 · 2024: 52 · 2023: 53 · 2022: 60 · 2021: 76 · 2020: 72 · 2019: 44 · 2018: 42 · 2017: 36 · 2016: 47 · 2015: 30 · 2014: 26
- FWCI
- 15.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- British Journal of Haematology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Celgene corporation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- lenalidomide, pomalidomide, cereblon, Ikaros, Aiolos, IKZF1, IKZF3, T cell costimulation, ubiquitination, proteasomal degradation, immunomodulators, pharmacodynamic biomarkers, T cells
- MeSH terms
- Lenalidomide, Humans, Immunologic Factors, Peptide Hydrolases, T-Lymphocytes, Thalidomide, Transcription Factors, Transfection, Angiogenesis Inhibitors, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Adaptor Proteins, Signal Transducing, Ikaros Transcription Factor, Ubiquitination
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
