Abstract
Targeted protein degradation refers to the use of small molecules to induce the selective degradation of proteins. In its most common form, this degradation is achieved through ligand-mediated neo-interactions between ubiquitin E3 ligases — the principal waste disposal machines of a cell — and the protein targets of interest, resulting in ubiquitylation and subsequent proteasomal degradation. Notable advances have been made in biological and mechanistic understanding of serendipitously discovered degraders. This improved understanding and novel chemistry has not only provided clinical proof of concept for targeted protein degradation but has also led to rapid growth of the field, with dozens of investigational drugs in active clinical trials. Two distinct classes of protein degradation therapeutics are being widely explored: bifunctional PROTACs and molecular glue degraders, both of which have their unique advantages and challenges. Here, we review the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. We also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take.
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References
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). This study, to our knowledge, provides the first conceptualization of PROTACs and the first proof-of-principle demonstration of degradation via a peptide-based PROTAC.
Zhao, L., Zhao, J., Zhong, K., Tong, A. & Jia, D. Targeted protein degradation: mechanisms, strategies and application. Signal Transduct. Target. Ther. 7, 113 (2022).
Chamberlain, P. P. et al. Structure of the human cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat. Struct. Mol. Biol. 21, 803–809 (2014). This study shows the crystal structure of cereblon bound to lenalidomide, revealing the binding site and of IMiD drugs.
Fischer, E. S. et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49–53 (2014). This study shows that the crystal structure of cereblon bound to thalidomide, lenalidomide and pomalidomide reveals the binding site of IMiD drugs and provides rationale for their activity.
Banik, S. M. et al. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 584, 291–297 (2020). This paper provides the first, to our knowledge, description of the LYTAC system and the first example of its use for the degradation of extracellular proteins.
Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010). This study identifies cereblon as the molecular target of thalidomide.
Kronke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014).
Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2014). Together with Kronke et al. (2014), this paper demonstrates that lenalidomide causes degradation of IKZF1 and IKZF3 in multiple myeloma cells.
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).
Takahashi, D. et al. AUTACs: cargo-specific degraders using selective autophagy. Mol. Cell 76, 797–810.e10 (2019).
Li, Z., Zhu, C., Ding, Y., Fei, Y. & Lu, B. ATTEC: a potential new approach to target proteinopathies. Autophagy 16, 185–187 (2020).
Bekes, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov. 21, 181–200 (2022).
Wu, T. et al. Targeted protein degradation as a powerful research tool in basic biology and drug target discovery. Nat. Struct. Mol. Biol. 27, 605–614 (2020).
Schey, S. A. et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J. Clin. Oncol. 22, 3269–3276 (2004).
Bartlett, J. B., Dredge, K. & Dalgleish, A. G. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat. Rev. Cancer 4, 314–322 (2004).
Mullard, A. Targeted protein degraders crowd into the clinic. Nat. Rev. Drug Discov. 20, 247–250 (2021).
Tan, X. et al. Mechanism of auxin perception by the TIR1 ubiquitin ligase. Nature 446, 640–645 (2007). This study provides structural evidence for the mechanism of action of the plant hormone auxin as a molecular glue degrader binding to the E3 ligase TIR1 and forming a ternary complex with IAA7.
Dikic, I. Proteasomal and autophagic degradation systems. Annu. Rev. Biochem. 86, 193–224 (2017).
Ciechanover, A. Intracellular protein degradation: from a vague idea, through the lysosome and the ubiquitin-proteasome system, and onto human diseases and drug targeting (Nobel lecture). Angew. Chem. Int. Ed. Engl. 44, 5944–5967 (2005).
Zheng, N. & Shabek, N. Ubiquitin ligases: structure, function, and regulation. Annu. Rev. Biochem. 86, 129–157 (2017).
Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).
Meyer, H. J. & Rape, M. Enhanced protein degradation by branched ubiquitin chains. Cell 157, 910–921 (2014).
Gu, X. et al. The midnolin-proteasome pathway catches proteins for ubiquitination-independent degradation. Science 381, eadh5021 (2023).
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 CRL4CRBN. Br. J. Haematol. 164, 811–821 (2014).
Blackledge, N. P. et al. Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell 157, 1445–1459 (2014).
Liu, C. et al. Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837–847 (2002).
Tanimoto, K., Makino, Y., Pereira, T. & Poellinger, L. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J. 19, 4298–4309 (2000).
Min, J. H. et al. Structure of an HIF-1α -pVHL complex: hydroxyproline recognition in signaling. Science 296, 1886–1889 (2002). This study provides structural evidence for HIF-1α hydroxyproline recognition by CRL2VHL E3 ubiquitin ligase.
Yen, H. C., Xu, Q., Chou, D. M., Zhao, Z. & Elledge, S. J. Global protein stability profiling in mammalian cells. Science 322, 918–923 (2008). This study describes functional genomics as a method to identify global protein stability with GFP fusion constructs.
Grau-Bove, X., Sebe-Pedros, A. & Ruiz-Trillo, I. The eukaryotic ancestor had a complex ubiquitin signaling system of archaeal origin. Mol. Biol. Evol. 32, 726–739 (2015).
Hua, Z. & Yu, P. Diversifying evolution of the ubiquitin-26s proteasome system in Brassicaceae and Poaceae. Int. J. Mol. Sci. 20, 3226 (2019).
Hua, Z. Diverse evolution in 111 plant genomes reveals purifying and dosage balancing selection models for F-box genes. Int. J. Mol. Sci. 22, 871 (2021).
Simpson, L. M. et al. Target protein localization and its impact on PROTAC-mediated degradation. Cell Chem. Biol. 29, 1482–1504.e7 (2022).
Donovan, K. A. et al. Mapping the degradable kinome provides a resource for expedited degrader development. Cell 183, 1714–1731.e10 (2020). This study demonstrates the global proteomic characterization of depth and selectivity of degradation of kinases using PROTAC approach.
Mayor-Ruiz, C. et al. Plasticity of the cullin-RING ligase repertoire shapes sensitivity to ligand-induced protein degradation. Mol. Cell 75, 849–858.e8 (2019).
Mahon, C., Krogan, N. J., Craik, C. S. & Pick, E. Cullin E3 ligases and their rewiring by viral factors. Biomolecules 4, 897–930 (2014).
Huh, K. et al. Human papillomavirus type 16 E7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor. J. Virol. 81, 9737–9747 (2007).
Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129–1136 (1990).
Jager, S. et al. Vif hijacks CBF-β to degrade APOBEC3G and promote HIV-1 infection. Nature 481, 371–375 (2011).
Zhang, S. et al. HIV-1 viral protein R downregulates Ebp1 and stabilizes p53 in glioblastoma U87MG cells. Clin. Transl. Oncol. 16, 293–300 (2014).
Ito, F. et al. Structural basis for HIV-1 antagonism of host APOBEC3G via cullin E3 ligase. Sci. Adv. 9, eade3168 (2023).
Li, Y. L. et al. The structural basis for HIV-1 Vif antagonism of human APOBEC3G. Nature 615, 728–733 (2023). Together with Ito et al. (2023), this paper provides structural description of RNA acting as a molecular glue degrader between the human E3 ubiquitin ligase CRL5–EloB–EloC bound to viral factor Vif and human transcription factor CBFβ targeting human protein substrate APOBEC3G for degradation.
Teale, W. D., Paponov, I. A. & Palme, K. Auxin in action: signalling, transport and the control of plant growth and development. Nat. Rev. Mol. Cell Biol. 7, 847–859 (2006).
Dharmasiri, N., Dharmasiri, S. & Estelle, M. The F-box protein TIR1 is an auxin receptor. Nature 435, 441–445 (2005).
Kepinski, S. & Leyser, O. The Arabidopsis F-box protein TIR1 is an auxin receptor. Nature 435, 446–451 (2005).
Abel, S. & Theologis, A. Early genes and auxin action. Plant Physiol. 111, 9–17 (1996).
Nishimura, K., Fukagawa, T., Takisawa, H., Kakimoto, T. & Kanemaki, M. An auxin-based degron system for the rapid depletion of proteins in nonplant cells. Nat. Methods 6, 917–922 (2009).
Manford, A. G. et al. Structural basis and regulation of the reductive stress response. Cell 184, 5375–5390.e16 (2021).
Lecoquierre, F. et al. Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants. Genet. Med. 21, 2504–2511 (2019).
Sakamoto, K. M. et al. Development of PROTACs to target cancer-promoting proteins for ubiquitination and degradation. Mol. Cell Proteom. 2, 1350–1358 (2003).
Schneekloth, A. R., Pucheault, M., Tae, H. S. & Crews, C. M. Targeted intracellular protein degradation induced by a small molecule: en route to chemical proteomics. Bioorg. Med. Chem. Lett. 18, 5904–5908 (2008). This paper, to our knowledge, shows the first description and validation of small molecule-based PROTAC.
Buckley, D. L. et al. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction. J. Am. Chem. Soc. 134, 4465–4468 (2012).
Hornberger, K. R. & Araujo, E. M. V. Physicochemical property determinants of oral absorption for PROTAC protein degraders. J. Med. Chem. 66, 8281–8287 (2023).
Winter, G. E. et al. Drug development. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015).
Lu, J. et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22, 755–763 (2015).
Zengerle, M., Chan, K. H. & Ciulli, A. Selective small molecule induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 10, 1770–1777 (2015). Together with Winter et al. (2015) and Lu et al. (2015), this paper shows the proof-of-principle demonstration that IMiD molecules can be conjugated to target binders and turned into efficient PROTACs.
Hines, J., Lartigue, S., Dong, H., Qian, Y. & Crews, C. M. MDM2-recruiting PROTAC offers superior, synergistic antiproliferative activity via simultaneous degradation of BRD4 and stabilization of p53. Cancer Res. 79, 251–262 (2019).
Han, X., Wei, W. & Sun, Y. PROTAC degraders with ligands recruiting MDM2 E3 ubiquitin ligase: an updated perspective. Acta Mater. Med. 1, 244–259 (2022).
Zhang, X. et al. Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines. Eur. J. Med. Chem. 199, 112397 (2020).
Wang, C. et al. Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents. J. Enzym. Inhib. Med. Chem. 37, 1437–1453 (2022).
Khan, S. et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 25, 1938–1947 (2019).
Huang, H. T. et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem. Biol. 25, 88–99.e6 (2018).
Liu, Z. et al. An overview of PROTACs: a promising drug discovery paradigm. Mol. Biomed. 3, 46 (2022).
Qi, S. M. et al. PROTAC: an effective targeted protein degradation strategy for cancer therapy. Front. Pharmacol. 12, 692574 (2021).
Singhal, S. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 341, 1565–1571 (1999).
Dimopoulos, M. A., Anagnostopoulos, A. & Weber, D. Treatment of plasma cell dyscrasias with thalidomide and its derivatives. J. Clin. Oncol. 21, 4444–4454 (2003).
Rehman, W., Arfons, L. M. & Lazarus, H. M. The rise, fall and subsequent triumph of thalidomide: lessons learned in drug development. Ther. Adv. Hematol. 2, 291–308 (2011).
McBride, W. G. Thalidomide and congenital abnormalities. Lancet 278, 1358 (1961).
Lenz, W., Pfeiffer, R. A., Kosenow, W. & Hayman, D. J. Thalidomide and congenital abnormalities. Lancet 279, 45–46 (1962).
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).
Pan, B. & Lentzsch, S. The application and biology of immunomodulatory drugs (IMiDs) in cancer. Pharmacol. Ther. 136, 56–68 (2012).
Holstein, S. A. & McCarthy, P. L. Immunomodulatory drugs in multiple myeloma: mechanisms of action and clinical experience. Drugs 77, 505–520 (2017).
Petzold, G., Fischer, E. S. & Thoma, N. H. Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase. Nature 532, 127–130 (2016). This paper provides structural description of cereblon lenalidomide-induced ternary complex and degradation of CK1α.
Matyskiela, M. E. et al. A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature 535, 252–257 (2016). This paper provides structural characterization of cereblon ternary complex and degradation of GSPT1 induced by CC-885.
Teng, M. & Gray, N. S. The rise of degrader drugs. Cell Chem. Biol. 30, 864–878 (2023).
Sievers, Q. L. et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, eaat0572 (2018).
Matyskiela, M. E. et al. Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex. Nat. Struct. Mol. Biol. 27, 319–322 (2020). This paper provides structural characterization of cereblon ternary complex and degradation of SALL4 induced by pomalidomide.
Furihata, H. et al. Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide. Nat. Commun. 11, 4578 (2020).
Sellar, R. S. et al. Degradation of GSPT1 causes TP53-independent cell death in leukemia while sparing normal hematopoietic stem cells. J. Clin. Invest. 132, e153514 (2022).
Bonazzi, S. et al. Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy. Cell Chem. Biol. 30, 235–247.e12 (2023).
Wang, E. S. et al. Acute pharmacological degradation of Helios destabilizes regulatory T cells. Nat. Chem. Biol. 17, 711–717 (2021). This study demonstrates structure-based design for cereblon molecular glue degraders targeting IKZF2.
Tuan, M. N. et al. Proteolysis targeting chimeras with reduced off-targets. Nat. Chem. 16, 218–228 (2023).
Fasching, B., Ryckmans, T. & Ritzén, A. Compounds that mediate protein degradation and methods of use thereof. US patent WO2023069700A1 (2022).
Nowak, R. P. et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14, 706–714 (2018).
Donovan, K. A. et al. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane radial ray syndrome. eLife 7, e38430 (2018). This paper identifies SALL4 as a transcription factor implicated in genetic diseases such as Duane radial ray syndrome that phenocopies thalidomide teratogenicity, as a protein degraded by thalidomide.
Matyskiela, M. E. et al. SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate. Nat. Chem. Biol. 14, 981–987 (2018).
Fink, E. C. et al. CrbnI391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice. Blood 132, 1535–1544 (2018).
Ichikawa, S. et al. The E3 ligase adapter cereblon targets the C-terminal cyclic imide degron. Nature 610, 775–782 (2022).
Heim, C., Spring, A. K., Kirchgassner, S., Schwarzer, D. & Hartmann, M. D. Identification and structural basis of C-terminal cyclic imides as natural degrons for cereblon. Biochem. Biophys. Res. Commun. 637, 66–72 (2022).
Oleinikovas, V., Gainza, P., Ryckmans, T., Fasching, B. & Thoma, N. H. From thalidomide to rational molecular glue design for targeted protein degradation. Annu. Rev. Pharmacol. Toxicol. 64, 291–312 (2024).
Heim, C., Spring, A. K., Kirchgassner, S., Schwarzer, D. & Hartmann, M. D. Cereblon neo-substrate binding mimics the recognition of the cyclic imide degron. Biochem. Biophys. Res. Commun. 646, 30–35 (2023).
Ichikawa, S. et al. The cyclimids: degron-inspired cereblon binders for targeted protein degradation. Cell Chem. Biol. https://doi.org/10.1016/j.chembiol.2024.01.003 (2024).
Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, eaal3755 (2017).
Uehara, T. et al. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat. Chem. Biol. 13, 675–680 (2017). Together with Han et al. (2017), this study identifies a new molecular glue degrader class of sulfonamides that bind DCAF15, a substrate receptor of CRL4DCAF15 E3 ubiquitin ligase, resulting in degradation of a splicing factor RBM39.
Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep. 29, 1499–1510.e6 (2019).
Gosavi, P. M. et al. Profiling the landscape of drug resistance mutations in neosubstrates to molecular glue degraders. ACS Cent. Sci. 8, 417–429 (2022).
Bussiere, D. E. et al. Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat. Chem. Biol. 16, 15–23 (2020).
Faust, T. B. et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 16, 7–14 (2020).
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).
Slabicki, M. et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature 585, 293–297 (2020).
Kozicka, Z. et al. Design principles for cyclin K molecular glue degraders. Nat. Chem. Biol. 20, 93–107 (2023).
Lv, L. et al. Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. eLife 9, e59994 (2020).
Mayor-Ruiz, C. et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 16, 1199–1207 (2020).
Simonetta, K. R. et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat. Commun. 10, 1402 (2019). This paper, to our knowledge, provides the first report of prospective discovery of molecular glue degraders capable of strengthening a native interaction between phosphorylated β-catenin and β-TrCP.
Nusse, R. & Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017).
ANZCTR. A Phase 1, Randomized, Placebo-Controlled, Study Evaluate Safety, Pharmacokinetics, Pharmacodynamics Single Multiple Ascending Doses PLX-4545 Healthy Subjects. https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12623001265662 (ANZCTR, 2024).
Hansen, J. D. et al. Discovery of CRBN E3 ligase modulator CC-92480 for the treatment of relapsed and refractory multiple myeloma. J. Med. Chem. 63, 6648–6676 (2020).
Hanzl, A. et al. E3-specific degrader discovery by dynamic tracing of substrate receptor abundance. J. Am. Chem. Soc. 145, 1176–1184 (2023).
Mason, J. W. et al. DNA-encoded library-enabled discovery of proximity-inducing small molecules. Nat. Chem. Biol. 20, 170–179 (2024).
Kozicka, Z. & Thoma, N. H. Haven’t got a glue: protein surface variation for the design of molecular glue degraders. Cell Chem. Biol. 28, 1032–1047 (2021).
Domostegui, A., Nieto-Barrado, L., Perez-Lopez, C. & Mayor-Ruiz, C. Chasing molecular glue degraders: screening approaches. Chem. Soc. Rev. 51, 5498–5517 (2022).
Nawaz, Z., Lonard, D. M., Dennis, A. P., Smith, C. L. & O’Malley, B. W. Proteasome-dependent degradation of the human estrogen receptor. Proc. Natl Acad. Sci. 96, 1858–1862 (1999).
Wallace, A. D. & Cidlowski, J. A. Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. J. Biol. Chem. 276, 42714–42721 (2001).
Zhu, J. et al. Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor α (RARα) and oncogenic RARα fusion proteins. Proc. Natl Acad. Sci. USA 96, 14807–14812 (1999).
Tsai, J. M. et al. UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability. Mol. Cell 83, 2753–2767.e10 (2023).
Long, X. & Nephew, K. P. Fulvestrant (ICI 182,780)-dependent interacting proteins mediate immobilization and degradation of estrogen receptor-alpha. J. Biol. Chem. 281, 9607–9615 (2006).
Carlson, R. W. The history and mechanism of action of fulvestrant. Clin. Breast Cancer 6, S5–S8 (2005).
Nathan, M. R. & Schmid, P. A review of fulvestrant in breast cancer. Oncol. Ther. 5, 17–29 (2017).
Osborne, C. K., Wakeling, A. & Nicholson, R. I. Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br. J. Cancer 90, S2–S6 (2004).
Guan, J. et al. Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell 178, 949–963.e18 (2019).
Hilmi, K. et al. Role of SUMOylation in full antiestrogenicity. Mol. Cell. Biol. 32, 3823–3837 (2012).
Xiong, Y. et al. Chemo-proteomics exploration of HDAC degradability by small molecule degraders. Cell Chem. Biol. 28, 1514–1527.e4 (2021).
Lu, W. et al. Fragment-based covalent ligand discovery. RSC Chem. Biol. 2, 354–367 (2021).
Knight, S., Gianni, D. & Hendricks, A. Fragment-based screening: a new paradigm for ligand and target discovery. SLAS Discov. 27, 3–7 (2022).
Crowley, V. M., Thielert, M. & Cravatt, B. F. Functionalized scout fragments for site-specific covalent ligand discovery and optimization. ACS Cent. Sci. 7, 613–623 (2021).
Spradlin, J. N. et al. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat. Chem. Biol. 15, 747–755 (2019).
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).
Grimster, N. P. Covalent PROTACs: the best of both worlds? RSC Med. Chem. 12, 1452–1458 (2021).
Nowak, R. P. et al. Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead. RSC Chem. Biol. 4, 906–912 (2023).
Forte, N. et al. Targeted protein degradation through E2 recruitment. ACS Chem. Biol. 18, 897–904 (2023).
Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 468, 1067–1073 (2010).
Li, Y. D. et al. Template-assisted covalent modification of DCAF16 underlies activity of BRD4 molecular glue degraders. Preprint at bioRxiv https://doi.org/10.1101/2023.02.14.528208 (2023).
Shergalis, A. G. et al. CRISPR screen reveals BRD2/4 molecular glue-like degrader via recruitment of DCAF16. ACS Chem. Biol. 18, 331–339 (2023).
Hsia, O. et al. Targeted protein degradation via intramolecular bivalent glues. Nature 627, 204–211 (2024).
Kerres, N. et al. Chemically induced degradation of the oncogenic transcription factor BCL6. Cell Rep. 20, 2860–2875 (2017).
Slabicki, M. et al. Small-molecule-induced polymerization triggers degradation of BCL6. Nature 588, 164–168 (2020).
Zhang, X. W. et al. Arsenic trioxide controls the fate of the PML-RARα oncoprotein by directly binding PML. Science 328, 240–243 (2010).
Liquori, A. et al. Acute promyelocytic leukemia: a constellation of molecular events around a single PML-RARA fusion gene. Cancers 12, 624 (2020).
Martens, J. H. et al. PML-RARα/RXR alters the epigenetic landscape in acute promyelocytic leukemia. Cancer Cell 17, 173–185 (2010).
Ablain, J. et al. Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies. J. Exp. Med. 210, 647–653 (2013).
Bashore, C. et al. Targeted degradation via direct 26S proteasome recruitment. Nat. Chem. Biol. 19, 55–63 (2023).
Schiemer, J. et al. Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes. Nat. Chem. Biol. 17, 152–160 (2021).
Farnaby, W. et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat. Chem. Biol. 15, 672–680 (2019).
Kannt, A. & Dikic, I. Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation. Cell Chem. Biol. 28, 1014–1031 (2021).
Hoegenauer, K. et al. Discovery of ligands for TRIM58, a novel tissue-selective E3 ligase. ACS Med. Chem. Lett. 14, 1631–1639 (2023).
Okamoto, T., Imaizumi, K. & Kaneko, M. The role of tissue-specific ubiquitin ligases, RNF183, RNF186, RNF182 and RNF152, in disease and biological function. Int. J. Mol. Sci. 21, 3921 (2020).
Bondeson, D. P. et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 25, 78–87.e5 (2018).
Brand, M. et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem. Biol. 26, 300–306.e9 (2019).
Jiang, B. et al. Development of dual and selective degraders of cyclin-dependent kinases 4 and 6. Angew. Chem. Int. Ed. Engl. 58, 6321–6326 (2019).
Kofink, C. et al. A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo. Nat. Commun. 13, 5969 (2022).
Smith, B. E. et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat. Commun. 10, 131 (2019).
Tovell, H. et al. Design and characterization of SGK3-PROTAC1, an isoform specific SGK3 kinase PROTAC degrader. ACS Chem. Biol. 14, 2024–2034 (2019).
Jauslin, W. T. et al. A high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα. Chem. Sci. 15, 683–691 (2024).
Hu, R. et al. Identification of a selective BRD4 PROTAC with potent antiproliferative effects in AR-positive prostate cancer based on a dual BET/PLK1 inhibitor. Eur. J. Med. Chem. 227, 113922 (2022).
Cantley, J. et al. Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers. Nat. Commun. 13, 6814 (2022).
Sperling, A. S. et al. Patterns of substrate affinity, competition, and degradation kinetics underlie biological activity of thalidomide analogs. Blood 134, 160–170 (2019).
Liang, R. et al. ICP-490 is a highly potent and selective IKZF1/3 degrader with robust anti-tumor activities against multiple myeloma and non-Hodgkin’s lymphoma. Cancer Res. 83, abstr. 3427 (2023).
Michot, J.-M. et al. Clinical activity of CC-99282, a novel, oral small molecule cereblon E3 ligase modulator (CELMoD) agent, in patients (Pts) with relapsed or refractory non-Hodgkin lymphoma (R/R NHL) - first results from a phase 1, open-label study. Blood 138, 3574–3574 (2021).
Lonial, S. et al. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. Lancet Haematol. 9, e822–e832 (2022).
Richardson, P. G. et al. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N. Engl. J. Med. 389, 1009–1022 (2023).
Berdeja, J. et al. A phase 1 study of CFT7455, a novel degrader of IKZF1/3, in multiple myeloma and non-Hodgkin lymphoma. Blood 138, 1675–1675 (2021).
Bewersdorf, J. P. et al. A phase II clinical trial of E7820 for patients with relapsed/refractory myeloid malignancies with mutations in splicing factor genes. Blood 140, 9065–9067 (2022).
Hamilton, E. P. et al. ARV-471, an estrogen receptor (ER) PROTAC degrader, combined with palbociclib in advanced ER+/human epidermal growth factor receptor 2-negative (HER2−) breast cancer: phase 1b cohort (part C) of a phase 1/2 study. J. Clin. Oncol. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS1120 (2022).
Mato, A. et al. A first-in-human phase 1 trial of NX-2127, a first-in-class oral BTK degrader with IMiD-like activity, in patients with relapsed and refractory B-cell malignancies. J. Clin. Oncol. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS7581 (2022).
Mato, A. R. et al. NX-2127-001, a first-in-human trial of NX-2127, a Bruton’s tyrosine kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies. Blood 140, 2329–2332 (2022).
Linton, K. et al. Pb2331: an ongoing first-in-human phase 1 trial of Nx-5948, an oral Bruton’s tyrosine kinase (Btk) degrader, in patients with relapsed/refractory B cell malignancies. HemaSphere 7, e29005fd (2023).
Starodub, A. et al. Phase 1 study of KT-333, a targeted protein degrader, in patients with relapsed or refractory lymphomas, large granular lymphocytic leukemia, and solid tumors. J. Clin. Oncol. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS3171 (2022).
Stevens, D. A. et al. Phase 1 study of KT-413, a targeted protein degrader, in adult patients with relapsed or refractory B-cell non-Hodgkin lymphoma. J. Clin. Oncol. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS3170 (2022).
Gao, X. et al. Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. 40, 17–17 (2022).
Petrylak, D. P. et al. A phase 2 expansion study of ARV-766, a PROTAC androgen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol. https://doi.org/10.1200/JCO.2023.41.6_suppl.TPS290 (2023).
Robbins, D. W. et al. Discovery and preclinical pharmacology of NX-2127, an orally bioavailable degrader of Bruton’s tyrosine kinase with immunomodulatory activity for the treatment of patients with B cell malignancies. J. Med. Chem. 67, 2321–2336 (2024).
Yang, Z. et al. Merging PROTAC and molecular glue for degrading BTK and GSPT1 proteins concurrently. Cell Res. 31, 1315–1318 (2021).
Lenz, W. A short history of thalidomide embryopathy. Teratology 38, 203–215 (1988).
Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101–114 (2017).
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).
Bjorklund, C. C. et al. Evidence of a role for activation of Wnt/β-catenin signaling in the resistance of plasma cells to lenalidomide. J. Biol. Chem. 286, 11009–11020 (2011).
Bjorklund, C. C. et al. Evidence of a role for CD44 and cell adhesion in mediating resistance to lenalidomide in multiple myeloma: therapeutic implications. Leukemia 28, 373–383 (2014).
Ocio, E. M. et al. In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone. Leukemia 29, 705–714 (2015).
Wei, S. et al. Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion. Oncogene 32, 1110–1120 (2013).
Martinez-Hoyer, S. & Karsan, A. Mechanisms of lenalidomide sensitivity and resistance. Exp. Hematol. 91, 22–31 (2020).
Kortum, 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).
Kurimchak, A. M. et al. The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells. Sci. Signal. 15, eabn2707 (2022).
Zhang, J. et al. Assessing IRAK4 functions in ABC DLBCL by IRAK4 kinase inhibition and protein degradation. Cell Chem. Biol. 27, e1513 (2020).
Chen, Y. et al. Design, synthesis, and biological evaluation of IRAK4-targeting PROTACs. ACS Med. Chem. Lett. 12, 82–87 (2021).
Nunes, J. et al. Targeting IRAK4 for degradation with PROTACs. ACS Med. Chem. Lett. 10, 1081–1085 (2019).
Yamashita, H. et al. Application of protein knockdown strategy targeting β-sheet structure to multiple disease-associated polyglutamine proteins. Bioorg. Med. Chem. 28, 115175 (2020).
Gao, N., Chen, Y. X., Zhao, Y. F. & Li, Y. M. Chemical methods to knock down the amyloid proteins. Molecules 22, 916 (2017).
Hyun, S. & Shin, D. Chemical-mediated targeted protein degradation in neurodegenerative diseases. Life 11, 607 (2021).
Tomoshige, S., Nomura, S., Ohgane, K., Hashimoto, Y. & Ishikawa, M. Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole derivative. Bioorg. Med. Chem. Lett. 28, 707–710 (2018).
Lu, M. et al. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. Eur. J. Med. Chem. 146, 251–259 (2018).
Tomoshige, S., Nomura, S., Ohgane, K., Hashimoto, Y. & Ishikawa, M. Discovery of small molecules that induce the degradation of huntingtin. Angew. Chem. Int. Ed. Engl. 56, 11530–11533 (2017).
Fan, X., Jin, W. Y., Lu, J., Wang, J. & Wang, Y. T. Rapid and reversible knockdown of endogenous proteins by peptide-directed lysosomal degradation. Nat. Neurosci. 17, 471–480 (2014).
Zou, C. et al. The human E3 ligase RNF185 is a regulator of the SARS-CoV-2 envelope protein. iScience 26, 106601 (2023).
Espinoza-Chavez, R. M. et al. Targeted protein degradation for infectious diseases: from basic biology to drug discovery. ACS Bio Med Chem Au 3, 32–45 (2023).
de Wispelaere, M. et al. Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations. Nat. Commun. 10, 3468 (2019). This paper, to our knowledge, provides the first report of PROTAC molecules targeting viral proteins for degradation using human host degradation machinery.
Zhao, J. et al. An anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA. Nat. Commun. 13, 2079 (2022).
Xu, Z. et al. Discovery of oseltamivir-based novel PROTACs as degraders targeting neuraminidase to combat H1N1 influenza virus. Cell Insight 1, 100030 (2022).
Morreale, F. E. et al. BacPROTACs mediate targeted protein degradation in bacteria. Cell 185, 2338–2353.e18 (2022). This paper provides proof of principle of BacPROTAC-induced protein degradation in bacteria using bacterial protease machinery.
Hoi, D. M. et al. Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival. Cell 186, 2176–2192.e22 (2023).
Ding, Y., Fei, Y. & Lu, B. Emerging new concepts of degrader technologies. Trends Pharmacol. Sci. 41, 464–474 (2020).
Sasso, J. M. et al. Molecular glues: the adhesive connecting targeted protein degradation to the clinic. Biochemistry 62, 601–623 (2023).
Chamberlain, P. P. et al. Evolution of cereblon-mediated protein degradation as a therapeutic modality. ACS Med. Chem. Lett. 10, 1592–1602 (2019).
Imaide, S. et al. Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity. Nat. Chem. Biol. 17, 1157–1167 (2021).
Gourisankar, S. et al. Rewiring cancer drivers to activate apoptosis. Nature 620, 417–425 (2023).
Raina, K. et al. Regulated induced proximity targeting chimeras (RIPTACs): a novel heterobifunctional small molecule therapeutic strategy for killing cancer cells selectively. Preprint at bioRxiv https://doi.org/10.1101/2023.01.01.522436 (2023).
Wang, W. W. et al. Targeted protein acetylation in cells using heterobifunctional molecules. J. Am. Chem. Soc. 143, 16700–16708 (2021).
Soumbasis, A., Eldeeb, M. A., Ragheb, M. A. & Zorca, C. E. Dephosphorylation targeting chimaera (DEPTAC): targeting tau proteins in tauopathies. Curr. Protein Pept. Sci. 23, 129–132 (2022).
Zhang, Q. et al. Protein phosphatase 5-recruiting chimeras for accelerating apoptosis-signal-regulated kinase 1 dephosphorylation with antiproliferative activity. J. Am. Chem. Soc. 145, 1118–1128 (2023).
Chen, P. H. et al. Modulation of phosphoprotein activity by phosphorylation targeting chimeras (PhosTACs). ACS Chem. Biol. 16, 2808–2815 (2021).
Siriwardena, S. U. et al. Phosphorylation-inducing chimeric small molecules. J. Am. Chem. Soc. 142, 14052–14057 (2020).
Henning, N. J. et al. Deubiquitinase-targeting chimeras for targeted protein stabilization. Nat. Chem. Biol. 18, 412–421 (2022).
Gadd, M. S. et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13, 514–521 (2017). This study provides the first, to our knowledge, crystal structure of CRL2VHL E3 ubiquitin ligase in complex with MZ-1 and neo-substrate BRD4BD2; the ternary complex is shown to exhibit positive cooperativity resulting in efficient degradation.
Gao, Y. et al. Catalytic degraders effectively address kinase site mutations in EML4-ALK oncogenic fusions. J. Med. Chem. 66, 5524–5535 (2023).
Ahn, G. et al. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat. Chem. Biol. 17, 937–946 (2021).
Nabet, B. et al. Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules. Nat. Commun. 11, 4687 (2020).
Acknowledgements
We thank all members of the Fischer and Ebert labs for the discussions and input. R.P.N. is a member of the excellence cluster ImmunoSensation2 funded by the Deutsche Forschungsgemeinschaft (DFG) under Germany’s Excellence Strategy — EXC2151–390873048.
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The authors contributed equally to all aspects of the article.
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Competing interests
E.S.F. is a founder, member of the scientific advisory board and equity holder of Civetta Therapeutics, Proximity Therapeutics and Neomorph, Inc. (also board of directors). He is an equity holder and scientific advisory board member for Avilar Therapeutics and Photys Therapeutics, an equity holder in Lighthorse Therapeutics and a consultant to Novartis, Sanofi, EcoR1 Capital, Ajax, Odyssey and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Bayer, Interline and Astellas. B.L.E. has received research funding from Celgene, Deerfield, Novartis and Calico and consulting fees from GRAIL. He is a member of the scientific advisory board and shareholder for Neomorph Inc., TenSixteen Bio, Skyhawk Therapeutics and Exo Therapeutics. R.P.N. and J.M.T. declare no competing interests.
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Supplementary information
Glossary
- Acetylation tagging
-
(AceTAG). Acetylation tagging system in which heterobifunctional molecules composed of ligands to acetyltransferase p300/CBP are linked by binder to FKBP12F36V and can acetylate FKBP12F36V-tagged target proteins.
- Activity-based protein profiling
-
(ABPP). A proteomics-based technology that uses chemical probes, usually consisting of a reactive group (warhead), a chemical linker and a reporter group including a tag. Probes whose reactive groups react with target proteins are isolated and identified via proteomics.
- Antibody targeting chimaeras
-
(AbTACs). Recombinant bispecific antibodies that recruit E3 ligases bound to the membrane for degradation of cell-surface proteins.
- Cullin-RING E3 ubiquitin ligase
-
(CRL). Family of E3 ubiquitin ligases that contain a cullin protein (CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5 or CUL7). These multicomponent complexes frequently include adaptor proteins in between the substrate receptors.
- DDB1 and cullin-associated factor
-
(DCAF). Proteins associated with cullin proteins, such as substrate receptors or substrate adaptors, in CRLs.
- Dephosphorylation-targeting chimaeras
-
(DEPTACs). Heterobifunctional peptides that recruit a phosphatase to a target protein. The approach was demonstrated to dephosphorylate tau with chimaeric peptides composed of tau binding motif, linker, PP2A phosphatase binding motif and cell-penetrating sequence.
- Deubiquitinase-targeting chimaeras
-
(DUBTACs). Heterobifunctional small molecules consisting of a deubiquitinase recruiter and a target binder. A DUBTAC has been demonstrated to deubiquitinate ΔF508-CFTR by using a covalent allosteric OTUB1 recruiter linked to lumacaftor, a ΔF508-CFTR binding small molecule.
- Fragment-based ligand discovery
-
(FBLD). A ligand discovery approach that uses small chemical fragments instead of elaborated structures in an attempt to cover wider chemical spaces with fewer molecules. After initial low-affinity binding, fragments are discovered — often using chemoproteomics approaches; these fragments are elaborated (such as the addition of functional groups, atoms or other scaffolds) into larger molecules with improved binding affinity.
- Immunomodulatory imide drugs
-
(IMiDs). A group of drugs that include the small molecules thalidomide, lenalidomide and pomalidomide, known for their immunomodulatory functions. IMiDs bind CRBN and cause degradation of transcription factors including IKZF1/3.
- Lysosome-targeting chimaeras
-
(LYTACs). Antibodies modified with a lysosome-targeting ligand, such as the tri-GalNAc substrate of asialoglycoprotein receptor (ASGPR), thus enabling the internalization of the antibody bound with its protein target. LYTACs target cell surface proteins for lysosomal degradation.
- mRNA display technology
-
A display-based technique that evolves peptides or proteins that bind to a specific target. A DNA library is first synthesized with sites for T7 RNA polymerase transcription and ribosomal binding. DNA libraries are transcribed in vitro to an mRNA library and ligated to a DNA spacer attached to puromycin. The resulting library is translated in vitro to a peptide library that is covalently linked to the mRNA and selected for binding to an immobilized target. The mRNA–DNA duplex resulting from the bound peptides is sequenced and amplified with error-prone PCR to increase diversity of the mRNA library for the next iterative cycle.
- Nuclear co-activators
-
(NCOAs). A family of proteins that bind to nuclear hormone receptors to facilitate transcriptional activation. NCOAs often bind a conserved hydrophobic cleft within nuclear receptors, which allows them to engage a broad number of targets.
- Phosphate-recruiting chimaeras
-
(PhoRCs). Heterobifunctional small molecules that recruit phosphatase to a target protein. The PhoRC system was demonstrated with DDO3711, which is a bifunctional small molecule that binds phosphatase PP5 and recruits it to ASK1 via the active site inhibitor of ASK1.
- Phosphorylation inducing chimaeras
-
(PHICs). Heterobifunctional small molecules that recruit a kinase to a target protein. PHICs were demonstrated to phosphorylate BRD4 by recruitment of AMPK or PKC kinases.
- Phosphorylation-targeting chimaeras
-
(PhosTACs). Heterobifunctional small molecules that recruit phosphatase to a target protein. The PhosTAC approach was demonstrated using FKBP12F36V-tagged phosphatase and HaloTagged-target protein with a PhosTAC composed of FKBP12F36V small-molecule binder and a halo ligand.
- Regulated induced proximity targeting chimaeras
-
(RIPTACs). Bifunctional small molecules that bring into proximity two proteins, a disease-specific protein target with a pan-essential effector protein, resulting in context-specific toxicity.
- Sumolyation
-
Sumolyation is a post-translational modification that involves the attachment of SUMO proteins (SUMO1, SUMO2 or SUMO3), small ubiquitin-like peptides, to lysine residues that lead to different aspects of protein regulation and/or function. SUMO proteins are attached to targets in an analogous process to ubiquitin, via an E1, SUMO E2 and SUMO E3 ligases.
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Tsai, J.M., Nowak, R.P., Ebert, B.L. et al. Targeted protein degradation: from mechanisms to clinic. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00729-9
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DOI: https://doi.org/10.1038/s41580-024-00729-9