PROTAC targeted protein degraders: the past is prologue

In the paper

“Currently there are limited methods to selectively covalently bind to a protein56–58”

What the sources say

• Partly supported

  Section 3, “Achieving Bioorthogonality with Unique Amino Acid Sequences,” says single-site protein modification is difficult to achieve, supporting a limitation on highly selective covalent modification. But Section 2.1 describes routine protein conjugation and multiple selective residue-modification methods, so the paper does not establish that methods for selectively covalently modifying proteins are generally limited. Page numbers were not available in our copy. (LLM, conf=0.82)

  cites [56] Sletten, E. M. & Bertozzi, C. R. Bioorthogonal chemistry: fishing for selectivity in a sea of functionality. Angew. Chem. Int. Ed. Engl. 48, 6974–6998 (2009). sourceExperimental — accuracy not yet measured
• Not checked yetcites [57] Ray, S. & Murkin, A. S. New electrophiles and strategies for mechanism-based and targeted covalent inhibitor design. Biochemistry 58, 5234–5244 (2019). source
• Not checked yetcites [58] Lossouarn, A., Renard, P. Y. & Sabot, C. Tailored bioorthogonal and bioconjugate chemistry: a source of inspiration for developing kinetic target-guided synthesis strategies. Bioconjug Chem. 32, 63–72 (2021). source

In the paper

“Examples here include the approved IMiD class, which relies on CRBN to degrade IKZF1/IKZF3 (refs4,5) via a molecular glue mechanism”

What the sources say

• Partly supported

  The paper reports that lenalidomide promotes CRBN binding to IKZF1 and IKZF3, leading to their ubiquitination and degradation—a mechanism consistent with the citing sentence’s description of a molecular glue (Abstract, page not provided). It also reports that thalidomide binds CRBN and regulates IKZF1/IKZF3 levels, but does not establish the degradation mechanism for the entire approved IMiD class. (LLM, conf=0.83)

  cites [4] Kronke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014). sourceExperimental — accuracy not yet measured
• Supported

  The Discussion states that thalidomide, lenalidomide, and pomalidomide bind CRBN and induce CRL4CRBN-mediated degradation of IKZF1 and IKZF3. The Species-specific effects section describes IMiD binding as creating a site for substrate interactions, supporting the molecular-glue characterization. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [5] Kronke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature 523, 183–188 (2015). source

In the paper

“several central nervous system (CNS)-specific E3 ligases have emerged, such as RNF182 (ref.148) and tripartite motif-containing protein 9 (TRIM9)149”

What the sources say

• Partly supported

  The Results (‘The expression patterns of RNF182’; page not provided) report RNF182 expression in the tested CNS tissues but not in four tested non-CNS tissues, and the paper calls it ‘brain-enriched.’ The Results also demonstrate that RNF182 functions as an E3 ligase. This supports RNF182 as the example cited to this paper, but ‘CNS-specific’ is stronger than the tissue evidence establishes; TRIM9 has a separate citation in the citing sentence. (LLM, conf=0.83)

  cites [148] Liu, Q. Y., Lei, J. X., Sikorska, M. & Liu, R. A novel brain-enriched E3 ubiquitin ligase RNF182 is up regulated in the brains of Alzheimer’s patients and targets ATP6V0C for degradation. Mol. Neurodegener. 3, 4 (2008). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section describes TRIM9 as enriched in neurons, and the Introduction identifies TRIM proteins as E3 ubiquitin ligases. That supports the TRIM9 example, but enrichment does not establish the stronger claim that TRIM9 is CNS-specific. The separate RNF182 citation is not being judged here. (LLM, conf=0.83)

  cites [149] Menon, S. et al. The TRIM9/TRIM67 neuronal interactome reveals novel activators of morphogenesis. Mol. Biol. Cell 32, 314–330 (2021). sourceExperimental — accuracy not yet measured

In the paper

“With clinical proof-of-concept for PROTAC molecules against two well-established cancer targets provided in 2020, the field is poised to pursue targets that were previously considered ‘undruggable’.”

• Also stated in: § Introduction · plain

  “in 2020, these trials provided the first clinical proof-of-concept for the modality against two well-established cancer targets: the oestrogen receptor (ER) and the androgen receptor (AR).”

In the paper

“The subsequent discovery of a peptide from hypoxia-inducible factor 1 subunit-α (HIF1α) that bound the E3 ligase von Hippel–Lindau tumour suppressor (VHL)18,19 led to the design of cell-penetrating PROTACs that degraded a range of POIs.”

What the sources say

• Not checked yetcites [18] Hon, W. C. et al. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature 417, 975–978 (2002). source
• Not checked yetcites [19] Min, J. H. et al. Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling. Science 296, 1886–1889 (2002). source

In the paper

“In 2019, the first PROTAC molecules entered clinical testing; in 2020, these trials provided the first clinical proof-of-concept for the modality against two well-established cancer targets: the oestrogen receptor (ER) and the androgen receptor (AR).”

In the paper

“Protac-1 acted as a tether between METAP2 and β-TRCP, enabling the ligase to ubiquitylate METAP2 in extracts from unfertilized Xenopus laevis eggs.”

What the sources say

• Not checked yetcites [9] Sakamoto, K. M. et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl Acad. Sci. USA 98, 8554–8559 (2001). source

In the paper

“In parallel with the development of these early PROTAC molecules, the E3 ligase cereblon (CRBN) was identified as the target of thalidomide and its analogues lenalidomide and pomalidomide6, which are known as immunomodulatory imide drugs (IMiDs) in the context of cancer therapy.”

What the sources say

• Not checked yetcites [6] Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010). source

In the paper

“In this pathway, proteins are targeted for degradation by the proteasome in a three-step process involving ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2) and, finally, ubiquitin–protein ligases (E3), which coordinate the transfer of ubiquitin molecules to the target protein (substrate)14.”

What the sources say

• Not checked yetcites [14] Ciechanover, A., Orian, A. & Schwartz, A. L. Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays 22, 442–451 (2000). source

In the paper

“The concept of harnessing this natural degradation system for therapeutic purposes was inspired by early studies of viruses and plants (Box 2), which highlighted the possibility of deliberately designing small molecules that co-opt E3 ligases and recruit them for degradation of a POI.”

In the paper

“One involved using ligase-recruiting ligands to probe the biology and phenotype of a POI as an alternative to targeted inhibition, gene knockout or gene knockdown.”

In the paper

“Auxin acts by stabilizing the interaction between Aux/IAA proteins and the plant E3 ligase transport inhibitor response 1 (Tir1)239,240.”

What the sources say

• Not checked yetcites [239] Dharmasiri, N., Dharmasiri, S. & Estelle, M. The F-box protein TIR1 is an auxin receptor. Nature 435, 441–445 (2005). source
• Not checked yetcites [240] Kepinski, S. & Leyser, O. Auxin-induced SCFTIR1-Aux/IAA interaction involves stable modification of the SCFTIR1 complex. Proc. Natl Acad. Sci. USA 101, 12381–12386 (2004). source

In the paper

“More recently, targeted discovery of degrader compounds against oncoproteins in a cell-based system has enabled the discovery of novel cereblon (CRBN)-dependent and CRBN-independent IKAROS family zinc finger 1 (IKZF1) degraders235, suggesting that screening for degraders against a target of choice is a strategy that can yield a bounty of phenotypically relevant degrader molecules.”

What the sources say

• Not checked yetcites [235] Koduri, V. et al. Targeting oncoproteins with a positive selection assay for protein degraders. Sci. Adv. 7, eabd6263 (2021). source

In the paper

“In vitro proof of concept for the first fully synthetic PROTAC, dubbed Protac-1, was reported in 2001 (ref.9).”

What the sources say

• Not checked yetcites [9] Sakamoto, K. M. et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl Acad. Sci. USA 98, 8554–8559 (2001). source

In the paper

“The first rational discovery of molecular glues between a ligase and a substrate involved a series of compounds that restored binding affinity between the β-TRCP ligase and its mutated phospho-degron, discovered in a biochemical screen234.”

What the sources say

• Not checked yetcites [234] Simonetta, K. R. et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat. Commun. 10, 1402 (2019). source

In the paper

“The ER in breast cancer38,39 and the AR in prostate cancer33 are the leading examples of such targets.”

What the sources say

• Not checked yetcites [38] McDonnell, D. P., Wardell, S. E. & Norris, J. D. Oral selective estrogen receptor downregulators (SERDs), a breakthrough endocrine therapy for breast cancer. J. Med. Chem. 58, 4883–4887 (2015). source
• Not checked yetcites [39] Ariazi, E. A., Ariazi, J. L., Cordera, F. & Jordan, V. C. Estrogen receptors as therapeutic targets in breast cancer. Curr. Top. Med. Chem. 6, 181–202 (2006). source
• Not checked yetcites [33] Salami, J. et al. Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance. Commun. Biol. 1, 100 (2018). source

In the paper

“and ideally have an unstructured region that can be threaded into the proteasome.”

• Also stated in: § Targets best suited for degradation · plain

  “and ideally, an unstructured region to thread into the proteasome46,47.”

What the sources say

• Not checked yetcites [46] Guharoy, M., Bhowmick, P., Sallam, M. & Tompa, P. Tripartite degrons confer diversity and specificity on regulated protein degradation in the ubiquitin-proteasome system. Nat. Commun. 7, 10239 (2016). source
• Not checked yetcites [47] Davis, C., Spaller, B. L. & Matouschek, A. Mechanisms of substrate recognition by the 26S proteasome. Curr. Opin. Struct. Biol. 67, 161–169 (2021). source

In the paper

“ATTECs link a POI warhead to a ligand that binds to the autophagy protein LC3 (microtubule-associated protein 1 light chain 3α) glue, thereby bypassing the ubiquitin pathways by directly tethering the POI to the autophagosome.”

In the paper

“Twenty years after its theoretical conception, at least 15 targeted protein degraders, among them heterobifunctional PROTACs and molecular glues, had entered the clinic by the end of 2021 (ref.30) (Tables 1,2), and many more are expected to follow.”

What the sources say

• Not checked yetcites [30] Mullard, A. Targeted protein degraders crowd into the clinic. Nat. Rev. Drug Discov. 20, 247–250 (2021). source

In the paper

“The success of proteolysis-targeting chimeras (PROTACs) in hijacking the ubiquitin–proteasome system (UPS) for targeted protein degradation (TPD) has motivated research into other classes of heterobifunctional molecules that depend on non-UPS pathways to degrade a protein of interest (POI)246,247.”

What the sources say

• Not checked yetcites [246] Ding, Y., Fei, Y. & Lu, B. Emerging new concepts of degrader technologies. Trends Pharmacol. Sci. 41, 464–474 (2020). source
• Not checked yetcites [247] Kastl, J. M., Davies, G., Godsman, E. & Holdgate, G. A. Small-molecule degraders beyond PROTACs-challenges and opportunities. SLAS Discov. 26, 524–533 (2021). source

In the paper

“Although this has been a highly effective approach, it has left potential drug targets undrugged or underdrugged45.”

What the sources say

• Not checked yetcites [45] Hopkins, A. L. & Groom, C. R. The druggable genome. Nat. Rev. Drug Discov. 1, 727–730 (2002). source

In the paper

“The data also demonstrated ARV-110-mediated degradation of the protein target in tumours — the first such evidence for a PROTAC molecule in humans — and revealed early signs of antitumour activity, as measured by reductions in levels of prostate specific antigen (PSA) and/or by RECIST (Response Evaluation Criteria in Solid Tumors).”

What the sources say

• Not checked yetcites [40] Petrylak, D. P. et al. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI). J. Clin. Oncol. 38, 3500–3500 (2020). source

In the paper

“The interim data for ARV-471 revealed a manageable tolerability profile with robust signals of clinical efficacy41, a 42% clinical benefit rate in a heavily pretreated population and evidence of better ER degradation than fulvestrant and other clinical-stage selective ER degraders (SERDs) when compared at the same stage of development.”

What the sources say

• Not checked yetcites [41] Snyder, L. B. et al. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer. In Proc. 112th Annual Meeting of the American Association for Cancer Research 1116 (AACR, 2021). source

In the paper

“In 2020, initial positive data reported from the phase I trials of ARV-110 and ARV-471 answered all four foundational questions in the affirmative — not just for the compounds themselves but for the entire TPD field.”

In the paper

“The interim data for ARV-471 revealed a manageable tolerability profile with robust signals of clinical efficacy41, a 42% clinical benefit rate in a heavily pretreated population and evidence of better ER degradation than fulvestrant and other clinical-stage selective ER degraders (SERDs) when compared at the same stage of development.”

What the sources say

• Not checked yetcites [41] Snyder, L. B. et al. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer. In Proc. 112th Annual Meeting of the American Association for Cancer Research 1116 (AACR, 2021). source

In the paper

“Proteolysis-targeting chimeras (PROTACs) bring the protein degrader function to the target; they do not need to bind within a biologically functional active site.”

In the paper

“AbTACs are bispecific antibodies that recruit membrane-bound E3 ligases to a membrane POI for degradation by the lysosome degradation pathway.”

In the paper

“Although not heterobifunctional, these new-generation CRBN modulators have been engineered with therapeutic targets in mind (IKZF1/IKZF3 and G1 to S phase transition 1 (GSPT1)), which are recruited by the compounds in a molecular glue mechanism to target them for degradation (Box 1).”

In the paper

“The data also demonstrated ARV-110-mediated degradation of the protein target in tumours — the first such evidence for a PROTAC molecule in humans — and revealed early signs of antitumour activity, as measured by reductions in levels of prostate specific antigen (PSA) and/or by RECIST (Response Evaluation Criteria in Solid Tumors).”

What the sources say

• Not checked yetcites [40] Petrylak, D. P. et al. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI). J. Clin. Oncol. 38, 3500–3500 (2020). source

In the paper

“From a structural perspective, PROTAC targets need a small-molecule binding surface that is approachable by an E3 ligase”

• Also stated in: § Targets best suited for degradation · plain

  “Although ‘PROTACable’ POIs do not need an enzyme active site, they do need a small-molecule binding site that is approachable by an E3 ligase.”

In the paper

“The era of rationally designed targeted protein degraders as potential human therapeutics began in 2019 with the entry of two heterobifunctional degraders into first-in-human trials (Fig. 3): the PROTACs ARV-110 (NCT03888612) and ARV-471 (NCT04072952), targeting the AR and the ER, respectively.”

In the paper

“Proteins that may be best suited to therapeutic intervention by targeted protein degradation instead of stoichiometric inhibition include proteins with disease-causing gain of function owing to mutation, overexpression, aggregation or the differential expression or localization of protein isoforms.”

• Also stated in: § Targets best suited for degradation · plain

  “a change away from the natural state, via overexpression, mutation, aggregation, isoform expression or localization, that results in a disease-causing gain of function”

In the paper

“So, the initial wave of heterobifunctional degraders in the clinic (Table 1) has focused on proteins with a combination of well-characterized biological and biochemical properties, clinically validated roles in diseases with clear unmet medical need, and previously established clinical efficacy for their inhibition.”

In the paper

“In MDA-MB-231 cells, AC-1 induced the degradation of PDL1 via an RNF43- and lysosomal-dependent mechanism.”

What the sources say

• Not checked yetcites [251] Cotton, A. D., Nguyen, D. P., Gramespacher, J. A., Seiple, I. B. & Wells, J. A. Development of antibody-based PROTACs for the degradation of the cell-surface immune checkpoint protein PD-L1. J. Am. Chem. Soc. 143, 593–598 (2021). source

In the paper

“Initial trial data showed that ARV-110 was well tolerated at doses up to 420 mg.”

What the sources say

• Not checked yetcites [40] Petrylak, D. P. et al. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI). J. Clin. Oncol. 38, 3500–3500 (2020). source

In the paper

“AUTACs link a warhead for the POI to a guanine derivative that tags the protein for degradation by the autophagy machinery.”

In the paper

“LYTACs bind a membrane-bound POI and the extracellular domains of a lysosome-shuttling receptor, which then drags the POI into the lysosome for degradation.”

In the paper

“Bensimon et al.52 challenged this view by showing that multi-transmembrane proteins from the solute carrier (SLC) transporter family could be degraded using the dTAG technology53.”

What the sources say

• Not checked yetcites [52] Bensimon, A. et al. Targeted degradation of SLC transporters reveals amenability of multi-pass transmembrane proteins to ligand-induced proteolysis. Cell Chem. Biol. 27, 728–739 e729 (2020). source
• Not checked yetcites [53] 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

“PROTACs that covalently bind the POI lose the ability to turn over and act iteratively55”

What the sources say

• Not checked yetcites [55] Bond, M. J., Chu, L., Nalawansha, D. A., Li, K. & Crews, C. M. Targeted degradation of oncogenic KRAS(G12C) by VHL-recruiting PROTACs. ACS Cent. Sci. 6, 1367–1375 (2020). source

In the paper

“Recently, it was disclosed that both ARV-110 and ARV-471 use CRBN as the E3 ligase that is recruited to their respective targets, AR and ER, to catalyse their ubiquitylation and proteasomal degradation41,71.”

What the sources say

• Not checked yetcites [41] Snyder, L. B. et al. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer. In Proc. 112th Annual Meeting of the American Association for Cancer Research 1116 (AACR, 2021). source
• Not checked yetcites [71] Snyder, L. B. et al. Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer. In Proc. 112th Annual Meeting of the American Association for Cancer Research 1115 (AACR, 2021).

In the paper

“CRBN appears to be emerging as a preferred E3 ligase for the first wave of TPD therapeutics in clinical trials.”

What the sources say

• Not checked yetcites [3] Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2014). source
• Not checked yetcites [4] Kronke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014). source
• Not checked yetcites [72] Chamberlain, P. P. & Cathers, B. E. Cereblon modulators: low molecular weight inducers of protein degradation. Drug Discov. Today Technol. 31, 29–34 (2019). source
• Not checked yetcites [73] Matyskiela, M. E. et al. A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos. J. Med. Chem. 61, 535–542 (2018). source
• Not checked yetcites [74] Petzold, G., Fischer, E. S. & Thoma, N. H. Structural basis of lenalidomide-induced CK1alpha degradation by the CRL4(CRBN) ubiquitin ligase. Nature 532, 127–130 (2016). source

In the paper

“In general, PROTAC physicochemical property space falls beyond the ‘rule of 5’ (refs59,60) owing to the bifunctional nature of the molecules.”

What the sources say

• Not checked yetcites [59] Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26 (2001). source
• Not checked yetcites [60] Doak, B. C., Over, B., Giordanetto, F. & Kihlberg, J. Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. Chem. Biol. 21, 1115–1142 (2014). source

In the paper

“However, several orally bioavailable compounds have been developed that fall outside the rule of 5 parameters.”

In the paper

“Short linkers can be used to modulate PROTAC molecular weights67 and properties65”

What the sources say

• Not checked yetcites [67] Troup, R. I., Fallan, C. & Baud, M. G. J. Current strategies for the design of PROTAC linkers: a critical review. Explor. Target. Antitumor Ther. 1, 273–312 (2020). source
• Not checked yetcites [65] Han, X. et al. Strategies toward discovery of potent and orally bioavailable proteolysis targeting chimera degraders of androgen receptor for the treatment of prostate cancer. J. Med. Chem. 64, 12831–12854 (2021). source

In the paper

“Selection of the ligand-binding site is particularly important in the case of scaffolding proteins, where the POI may only be partially exposed within a given complex.”

In the paper

“More recently, Wang et al.54 showed that programmed cell death ligand 1 (PDL1) — an immune checkpoint protein that resides on the cell surface to carry out its natural function but circulates between the surface and the cytoplasm — could be degraded using a CRBN-based PROTAC linked to the BMS-37 PDL1 warhead in MC-38 cells.”

What the sources say

• Not checked yetcites [54] Wang, Y. et al. In vitro and in vivo degradation of programmed cell death ligand 1 (PD-L1) by a proteolysis targeting chimera (PROTAC). Bioorg. Chem. 111, 104833 (2021). source

In the paper

“PROTACs may also benefit from cooperative PPIs between the E3 ligase and the POI. This can have the advantages of improved potency49 and selectivity50.”

What the sources say

• Not checked yetcites [49] Bondeson, D. P. et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 25, 78–87 e75 (2018). source
• Not checked yetcites [50] Alabi, S. et al. Mutant-selective degradation by BRAF-targeting PROTACs. Nat. Commun. 12, 920 (2021).

In the paper

“Schneider et al.70 have provided the first systematic assessment of drug targets according to their ability to be degraded by PROTAC molecules.”

What the sources say

• Not checked yetcites [70] Schneider, M. et al. The PROTACtable genome. Nat. Rev. Drug Discov. 20, 789–797 (2021). source

In the paper

“Accordingly, it has become routine to generate and characterize a new degrader in cell culture experiments and animal models of disease, using either VHL or CRBN as a recruiting ligase93.”

What the sources say

• Not checked yetcites [93] Wang, Y., Jiang, X., Feng, F., Liu, W. & Sun, H. Degradation of proteins by PROTACs and other strategies. Acta Pharm. Sin. B 10, 207–238 (2020). source

In the paper

“In fact, not only CR8, but four separate classes of compounds, each discovered by a different screening method, were found to have molecular glue-like properties in potentiating the interaction of DDB1 and CDK12, resulting in CCNK degradation84–87.”

What the sources say

• Not checked yetcites [84] Lv, L. et al. Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. eLife 9, e59994 (2020).
• Not checked yetcites [85] Slabicki, M. et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature 585, 293–297 (2020). source
• Not checked yetcites [86] Mayor-Ruiz, C. et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 16, 1199–1207 (2020). source
• Not checked yetcites [87] Dieter, S. M. et al. Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. Cell Rep. 36, 109394 (2021). source

In the paper

“a unique class of cyclin-dependent kinase 12 (CDK12) inhibitors, exemplified by CR8, which, unexpectedly, has been shown to directly co-opt DDB1 as an E3 ligase for the degradation of cyclin K (CCNK)84–86.”

What the sources say

• Not checked yetcites [84] Lv, L. et al. Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. eLife 9, e59994 (2020).
• Not checked yetcites [85] Slabicki, M. et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature 585, 293–297 (2020). source
• Not checked yetcites [86] Mayor-Ruiz, C. et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 16, 1199–1207 (2020). source

In the paper

“and can potentially enable the employment of E3 ligases with unique characteristics that could offer advantages against a particular target or in a given therapeutic setting.”

In the paper

“The modular nature of such PROTACs could allow ‘ligase-hopping’ — the ability to swap ligase ‘handles’ that offer the most potent degradation and the best physicochemical properties”

In the paper

“HaloPROTACs, dTAGs and other degradation proof-of-concept strategies, such as the AID system, have been reviewed extensively elsewhere96,97 and now serve as crucial target validation tools when approaching a new therapeutic POI.”

What the sources say

• Not checked yetcites [96] Roth, S., Fulcher, L. J. & Sapkota, G. P. Advances in targeted degradation of endogenous proteins. Cell Mol. Life Sci. 76, 2761–2777 (2019). source
• Not checked yetcites [97] Prozzillo, Y. et al. Targeted protein degradation tools: overview and future perspectives. Biology (Basel) 9, 421 (2020).

In the paper

“These findings suggest that many more compounds, including those approved or already in the clinic, could have a hitherto overlooked degrader contribution to their mechanism of action.”

In the paper

“With more than 600 human ubiquitin E3 ligases79,80 to potentially explore”

What the sources say

• Not checked yetcites [79] Oh, E., Akopian, D. & Rape, M. Principles of ubiquitin-dependent signaling. Annu. Rev. Cell Dev. Biol. 34, 137–162 (2018). source
• Not checked yetcites [80] Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug. Discov. 18, 949–963 (2019). source

In the paper

“this creates concerns that tumour cells could mutate to evade degraders that rely on non-essential ligases, such as CRBN and VHL, whose genomic loss or deletion results in no discernible effect on cellular viability or phenotype as defined by CERES scores in DepMap98, for example.”

What the sources say

• Not checked yetcites [98] Pacini, C. et al. Integrated cross-study datasets of genetic dependencies in cancer. Nat. Commun. 12, 1661 (2021).

In the paper

“Although the generation of VHL- and CRBN-based PROTAC molecules as research tools has become routine, their preclinical and clinical development can still pose challenges.”

In the paper

“sulfonamides previously in clinical trials81,82 that have since been shown to use DCAF15 to degrade RBM39 (refs25,27,29), also via a molecular glue mechanism”

What the sources say

• Not checked yetcites [25] Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, eaal3755 (2017). source
• Not checked yetcites [27] Uehara, T. et al. Selective degradation of splicing factor CAPERalpha by anticancer sulfonamides. Nat. Chem. Biol. 13, 675–680 (2017). source
• Not checked yetcites [29] Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep. 29, 1499–1510 e1496 (2019). source

In the paper

“Although use of small-molecule PROTACs in an endogenous setting is limited to protein targets that have ligands available”

In the paper

“In fact, preclinical studies of degraders that use CRBN or VHL to target multiple protein classes have detected emerging resistance that occurs via mutation and/or downregulation of components of the ubiquitin ligase machinery99–101.”

What the sources say

• Not checked yetcites [99] Shirasaki, R. et al. Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins. Cell Rep. 34, 108532 (2021). source
• Not checked yetcites [100] Zhang, L., Riley-Gillis, B., Vijay, P. & Shen, Y. Acquired resistance to BET-PROTACs (proteolysis-targeting chimeras) caused by genomic alterations in core components of E3 ligase complexes. Mol. Cancer Ther. 18, 1302–1311 (2019). source
• Not checked yetcites [101] Ottis, P. et al. Cellular resistance mechanisms to targeted protein degradation converge toward impairment of the engaged ubiquitin transfer pathway. ACS Chem. Biol. 14, 2215–2223 (2019).

In the paper

“Similarly, in the clinical setting in multiple myeloma, resistance to IMiDs such as pomalidomide and lenalidomide has been shown to include genomic alterations in both the target protein (IKZF1/IKZF3) and components of the CRBN ligase machinery102,103.”

What the sources say

• Not checked yetcites [102] Gooding, S. et al. Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma. Blood 137, 232–237 (2021). source
• Not checked yetcites [103] Barrio, S. et al. IKZF1/3 and CRL4(CRBN) E3 ubiquitin ligase mutations and resistance to immunomodulatory drugs in multiple myeloma. Haematologica 105, e237–e241 (2020). source

In the paper

“Buckley et al.94 have developed a tagging system based on HaloTag fusions that can be targeted by HaloPROTACs”

What the sources say

• Not checked yetcites [94] 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

“a few additional ‘generic’ E3 ligases have been shown to be exploitable by PROTACs, using small-molecule covalent tools that specifically recruit the ligases to degrade the prototypical TPD substrate, BRD4; these ligases include ring finger protein 4 (RNF4)132, RNF114 (refs133–135), KEAP1 (refs136,137) and most recently, fem-1 homologue B (FEM1B)138.”

What the sources say

• Not checked yetcites [132] Ward, C. C. et al. Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications. ACS Chem. Biol. 14, 2430–2440 (2019). source
• Not checked yetcites [133] Spradlin, J. N. et al. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat. Chem. Biol. 15, 747–755 (2019). source
• Not checked yetcites [134] Luo, M. et al. Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function. Cell Chem. Biol. 28, 559–566 (2021). source
• Not checked yetcites [135] Tong, B. et al. A nimbolide-based kinase degrader preferentially degrades oncogenic BCR-ABL. ACS Chem. Biol. 15, 1788–1794 (2020). source
• Not checked yetcites [136] Tong, B. et al. Bardoxolone conjugation enables targeted protein degradation of BRD4. Sci. Rep. 10, 15543 (2020).
• Not checked yetcites [137] Wei, J. et al. Harnessing the E3 Ligase KEAP1 for targeted protein degradation. J. Am. Chem. Soc. 143, 15073–15083 (2021). source

In the paper

“Zeng et al.124 initially developed a covalent PROTAC (XY-4-88) based on ARS-1620, a KRAS(G12C)-binding covalent warhead, and thalidomide as the CRBN-recruiting ligand124.”

What the sources say

• Not checked yetcites [124] Zeng, M. et al. Exploring targeted degradation strategy for oncogenic KRAS(G12C). Cell Chem. Biol. 27, 19–31 e16 (2020). source

In the paper

“a nuclear E3 ligase, DCAF16, has been shown to restrict target degradation to the nucleus131.”

What the sources say

• Not checked yetcites [131] Zhang, X., Crowley, V. M., Wucherpfennig, T. G., Dix, M. M. & Cravatt, B. F. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat. Chem. Biol. 15, 737–746 (2019). source

In the paper

“the pairing of VHL versus CRBN for a given target can result in different degradation efficiencies49, as was first observed when targeting the fusion oncogene BCR–ABL by PROTACs118.”

What the sources say

• Not checked yetcites [49] Bondeson, D. P. et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 25, 78–87 e75 (2018). source
• Not checked yetcites [118] Lai, A. C. et al. Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew. Chem. Int. Ed. Engl. 55, 807–810 (2016). source

In the paper

“The different outcomes of these two studies could arise from the different KRAS warheads, the linker between the POI and E3 ligase warheads, and/or the choice of E3 ligase.”

In the paper

“It is therefore possible that one ligase in particular may be better than others for degrading a certain target.”

In the paper

“Currently, all PROTACs to date use just a handful of these non-specialized ligases, collated in an online database: PROTAC-DB92.”

What the sources say

• Not checked yetcites [92] Weng, G. et al. PROTAC-DB: an online database of PROTACs. Nucleic Acids Res. 49, D1381–D1387 (2021). source

In the paper

“Bond et al.55 developed a covalent VHL–KRAS(G12C) PROTAC (LC-2), based on the MRTX849 KRAS(G12C)-targeting warhead and a VHL ligand.”

What the sources say

• Not checked yetcites [55] Bond, M. J., Chu, L., Nalawansha, D. A., Li, K. & Crews, C. M. Targeted degradation of oncogenic KRAS(G12C) by VHL-recruiting PROTACs. ACS Cent. Sci. 6, 1367–1375 (2020). source

In the paper

“A remarkable example is the low expression of VHL in platelets”

What the sources say

• Not checked yetcites [152] Khan, S. et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 25, 1938–1947 (2019). source

In the paper

“these are of high interest in tackling targets in neuronal diseases, as discussed below, where CNS-specific therapeutic targeting is desirable to avoid systemic off-target and toxicity effects.”

In the paper

“several recent reviews have analysed and categorized publicly available datasets — such as GTEx, The Cancer Genome Atlas (TCGA), ProteinAtlas and others — for ligase expression in healthy and diseased states, to highlight ligases with clear and distinct expression profiles80,99,143,144.”

What the sources say

• Not checked yetcites [80] Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug. Discov. 18, 949–963 (2019). source
• Not checked yetcites [99] Shirasaki, R. et al. Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins. Cell Rep. 34, 108532 (2021). source
• Not checked yetcites [143] Khan, S. et al. PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics. Oncogene 39, 4909–4924 (2020). source
• Not checked yetcites [144] He, Y. et al. Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies. J. Hematol. Oncol. 13, 103 (2020). source

In the paper

“the definition of low-hanging fruit with respect to structural enablement of ligases has recently been redefined with the ground-breaking publication of artificial intelligence (AI)-driven tertiary structure prediction models from Google/DeepMind141 and RoseTTAFold142.”

What the sources say

• Not checked yetcites [141] Tunyasuvunakool, K. et al. Highly accurate protein structure prediction for the human proteome. Nature 596, 590–596 (2021). source
• Not checked yetcites [142] Baek, M. et al. Accurate prediction of protein structures and interactions using a three-track neural network. Science 373, 871–876 (2021). source

In the paper

“DT2216 is in phase I trials30”

What the sources say

• Not checked yetcites [30] Mullard, A. Targeted protein degraders crowd into the clinic. Nat. Rev. Drug Discov. 20, 247–250 (2021). source

In the paper

“some ligases exhibit ‘reverse specificity’ — low expression in some tissue or cell types — that may also be advantageous for protein degraders.”

In the paper

“which has been shown to occur for some CRBN- and VHL-recruiting PROTACs, as discussed previously.”

What the sources say

• Not checked yetcites [99] Shirasaki, R. et al. Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins. Cell Rep. 34, 108532 (2021). source
• Not checked yetcites [100] Zhang, L., Riley-Gillis, B., Vijay, P. & Shen, Y. Acquired resistance to BET-PROTACs (proteolysis-targeting chimeras) caused by genomic alterations in core components of E3 ligase complexes. Mol. Cancer Ther. 18, 1302–1311 (2019). source
• Not checked yetcites [101] Ottis, P. et al. Cellular resistance mechanisms to targeted protein degradation converge toward impairment of the engaged ubiquitin transfer pathway. ACS Chem. Biol. 14, 2215–2223 (2019).

In the paper

“there are several other ubiquitin ligases, enabled by structural and/or validated substrate information, that present a path for the development of small molecules that can ultimately be converted into PROTACs, yet await development as potential PROTACable ligases.”

In the paper

“Finally, cancer-testis antigens (CTAs) also comprise ubiquitin ligases that have restricted expression in the normal testis but are highly overexpressed across multiple cancer types154,155.”

What the sources say

• Not checked yetcites [154] Wei, R. et al. Cancer testis antigens in sarcoma: expression, function and immunotherapeutic application. Cancer Lett. 479, 54–60 (2020). source
• Not checked yetcites [155] Weon, J. L. & Potts, P. R. The MAGE protein family and cancer. Curr. Opin. Cell Biol. 37, 1–8 (2015). source

In the paper

“The advantage of ligases with these profiles is that tumour cells would be less able to develop ligase-based resistance to PROTACs”

In the paper

“These correlations can be drawn and have been shown by analysing CERES scores in DepMap98 of E3 ligases across multiple tumour cell lines.”

What the sources say

• Not checked yetcites [98] Pacini, C. et al. Integrated cross-study datasets of genetic dependencies in cancer. Nat. Commun. 12, 1661 (2021).

In the paper

“Often, but not always, tumour enrichment of an E3 ligase coincides with the dependence of the tumour on expression of that ligase.”

In the paper

“This has allowed the identification of E3 ligases and other UPS genes — some better-characterized than others, such as cell division cycle 20 (CDC20), cytosolic iron–sulfur assembly component 1 (CIAO1) and WD repeat-containing protein 82 (WDR82) — that exhibit high tumour essentiality across many different cancer cell types99.”

What the sources say

• Not checked yetcites [99] Shirasaki, R. et al. Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins. Cell Rep. 34, 108532 (2021). source

In the paper

“Although not all MAGE E3 ligases are tumour specific159”

What the sources say

• Not checked yetcites [159] Tacer, K. F. & Potts, P. R. Cellular and disease functions of the Prader-Willi syndrome gene MAGEL2. Biochem. J. 474, 2177–2190 (2017). source

In the paper

“Among the clearest examples of ligases with tissue-specific expression are kelch-like family member 40 (KLHL40) and KLHL41 in skeletal muscle145”

What the sources say

• Not checked yetcites [145] Ehrlich, K. C., Baribault, C. & Ehrlich, M. Epigenetics of muscle- and brain-specific expression of KLHL family genes. Int. J. Mol. Sci. 21, 8394 (2020). source

In the paper

“The exact mechanism of ubiquitylation for MRLs is not as well understood as the mechanism for CRLs, for which substrate recruitment by multiple adaptors and the molecular details of Ub transfer from E2–Ub to the target has been extensively characterized at the atomic level of an entire CRL1 complex106,117.”

What the sources say

• Not checked yetcites [106] Baek, K. et al. NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly. Nature 578, 461–466 (2020). source
• Not checked yetcites [117] Horn-Ghetko, D. et al. Ubiquitin ligation to F-box protein targets by SCF-RBR E3-E3 super-assembly. Nature 590, 671–676 (2021). source

In the paper

“ligases have other key characteristics, such as tissue and cell-type specificity, tumour enrichment and tumour essentiality (Fig. 6), that can offer opportunities for ‘niche’ ligase degrader development.”

In the paper

“FBXO44 and other tissue- or cell-enriched ligases nonetheless have exciting potential for TPD, because the affinity of their ligands could be tuned to engineer in the specificity towards the tissue of choice, even though some basal level of ligase expression exists ubiquitously.”

In the paper

“a concept originally proposed in the landmark PROTAC paper by Sakamoto et al.9 20 years ago.”

What the sources say

• Not checked yetcites [9] Sakamoto, K. M. et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl Acad. Sci. USA 98, 8554–8559 (2001). source

In the paper

“Although these antibody–PROTAC conjugates obviously lose the clear advantages of oral bioavailability and tunable dosing schedule of small-molecule PROTACs”

In the paper

“Particularly for IRAK4, its scaffolding role in Toll-like receptor (TLR) signalling around the myddosome is established165,172”

What the sources say

• Not checked yetcites [165] Zarrin, A. A., Bao, K., Lupardus, P. & Vucic, D. Kinase inhibition in autoimmunity and inflammation. Nat. Rev. Drug Discov. 20, 39–63 (2021). source
• Not checked yetcites [172] Qin, J., Jiang, Z., Qian, Y., Casanova, J. L. & Li, X. IRAK4 kinase activity is redundant for interleukin-1 (IL-1) receptor-associated kinase phosphorylation and IL-1 responsiveness. J. Biol. Chem. 279, 26748–26753 (2004). source

In the paper

“Of these, KT-474 from Kymera Therapeutics is the first to enter clinical trials (Table 1).”

What the sources say

• Not checked yetcites Table 1

In the paper

“and has been the subject of intense PROTAC molecule experimentation across academia and industry166–168”

What the sources say

• Not checked yetcites [166] Schiemer, J. et al. Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes. Nat. Chem. Biol. 17, 152–160 (2021). source
• Not checked yetcites [167] Zorba, A. et al. Delineating the role of cooperativity in the design of potent PROTACs for BTK. Proc. Natl Acad. Sci. USA 115, E7285–E7292 (2018). source
• Not checked yetcites [168] Tinworth, C. P. et al. PROTAC-mediated degradation of bruton’s tyrosine kinase is inhibited by covalent binding. ACS Chem. Biol. 14, 342–347 (2019). source

In the paper

“Herein lies one of the great advantages of PROTACs: owing to their event-driven (versus occupancy-driven) pharmacology, PROTACs may overcome insensitivity to such resistance mutations through catalytic degradation of the target.”

In the paper

“but given that PROTACs can comparatively achieve greater specificity with respect to off-target effects of some kinase inhibitors126,181”

What the sources say

• Not checked yetcites [126] Donovan, K. A. et al. Mapping the degradable kinome provides a resource for expedited degrader development. Cell 183, 1714–1731 e1710 (2020). source
• Not checked yetcites [181] Burslem, G. M. et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem. Biol. 25, 67–77 e63 (2018). source

In the paper

“and may only be addressable by PROTAC degraders, many of which have been described to date173–175.”

What the sources say

• Not checked yetcites [173] Zhang, J. et al. Assessing IRAK4 functions in ABC DLBCL by IRAK4 kinase inhibition and protein degradation. Cell Chem. Biol. 27, 1500–1509 e1513 (2020). source
• Not checked yetcites [174] Nunes, J. et al. Targeting IRAK4 for degradation with PROTACs. ACS Med. Chem. Lett. 10, 1081–1085 (2019). source
• Not checked yetcites [175] Chen, Y. et al. Design, synthesis, and biological evaluation of IRAK4-targeting PROTACs. ACS Med. Chem. Lett. 12, 82–87 (2021). source

In the paper

“the ADC approach can be valuable for potent and robust degraders that have poor physicochemical properties for parenteral administration.”

In the paper

“Dragovic et al.160–162 at Genentech have pushed this modality forward and successfully demonstrated tumour-specific targeting in two different cancer types with ADCs involving VHL–BRD4 PROTACs.”

What the sources say

• Not checked yetcites [160] Pillow, T. H. et al. Antibody conjugation of a chimeric BET degrader enables in vivo activity. ChemMedChem 15, 17–25 (2020). source
• Not checked yetcites [161] Dragovich, P. S. et al. Antibody-mediated delivery of chimeric BRD4 degraders. Part 2: improvement of in vitro antiproliferation activity and in vivo antitumor efficacy. J. Med. Chem. 64, 2576–2607 (2021). source
• Not checked yetcites [162] Dragovich, P. S. et al. Antibody-mediated delivery of chimeric BRD4 degraders. Part 1: exploration of antibody linker, payload loading, and payload molecular properties. J. Med. Chem. 64, 2534–2575 (2021). source

In the paper

“Most recently, PROTACs that target mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1; also known as HPK1) have been described with promising preclinical activity180”

What the sources say

• Not checked yetcites [180] Si, J. et al. Hematopoietic progenitor kinase1 (HPK1) mediates T cell dysfunction and is a druggable target for T cell-based immunotherapies. Cancer Cell 38, 551–566 e511 (2020). source

In the paper

“Here, the potential scaffolding role of IRAK4 is especially intriguing as a target, as inhibitors of its kinase function may not fully address the role of IRAK4 in these conditions.”

In the paper

“particularly because of emergence of the C481S resistance mutation in BTK that renders first-generation BTK inhibitors less effective169,170.”

What the sources say

• Not checked yetcites [169] Buhimschi, A. D. et al. Targeting the C481S ibrutinib-resistance mutation in Bruton’s tyrosine kinase using PROTAC-mediated degradation. Biochemistry 57, 3564–3575 (2018). source
• Not checked yetcites [170] Sun, Y. et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 28, 779–781 (2018). source

In the paper

“Degrader drugs currently on the market (the IMiD class) and the overwhelming majority of newly developed PROTACs and molecular glue compounds currently in clinical trials (Tables 1,2) target various types of cancer30,163.”

What the sources say

• Not checked yetcites [30] Mullard, A. Targeted protein degraders crowd into the clinic. Nat. Rev. Drug Discov. 20, 247–250 (2021). source
• Not checked yetcites [163] Jan, M., Sperling, A. S. & Ebert, B. L. Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide. Nat. Rev. Clin. Oncol. 18, 401–417 (2021). source
• Not checked yetcites Tables 1,2

In the paper

“A BTK degrader (NX-5948) and an IRAK4 degrader (KT-474) in phase I clinical trials (Table 1), from Nurix Therapeutics and Kymera Therapeutics, respectively, could treat patients with various immuno-inflammatory diseases, such as rheumatoid arthritis.”

What the sources say

• Not checked yetcites Table 1

In the paper

“PROTACs have the potential to be first-in-class medicines in immuno-oncology as small-molecule drugs that target immune cell activation to phenocopy PD1/PDL1-directed agents178,179.”

What the sources say

• Not checked yetcites [178] Wang, Y., Deng, S. & Xu, J. Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets. Cancer Biol. Med. 17, 583–598 (2020). source
• Not checked yetcites [179] Shifrut, E. et al. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function. Cell 175, 1958–1971 e1915 (2018). source

In the paper

“Although PROTACs are poised to become an important modality for certain target classes, there are POIs that do not have the small-molecule binding sites needed for this approach.”

In the paper

“In fact, in preclinical models, decreasing tau protein levels via ASO strategies185,186 and recently by engineered zinc-finger transcription factors187 was shown to be durable and to reverse tau pathology.”

What the sources say

• Not checked yetcites [185] DeVos, S. L. et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci. Transl. Med. 9, eaag0481 (2017). source
• Not checked yetcites [186] Yiannopoulou, K. G. & Papageorgiou, S. G. Current and future treatments in Alzheimer disease: an update. J. Cent. Nerv. Syst. Dis. 12, 1179573520907397 (2020). source
• Not checked yetcites [187] Wegmann, S. et al. Persistent repression of tau in the brain using engineered zinc finger protein transcription factors. Sci. Adv. 7, eabe1611 (2021). source