Surka, C. et al. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells. Blood 137, 661–677 (2021).
Google Scholar
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).
Google Scholar
Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 343, 305–309 (2014).
Google Scholar
Kronke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014).
Google Scholar
Kronke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS. Nature 523, 183–188 (2015).
Google Scholar
Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010).
Google Scholar
Fischer, E. S. et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49–53 (2014).
Google Scholar
Chamberlain, P. P. & Hamann, L. G. Development of targeted protein degradation therapeutics. Nat. Chem. Biol. 15, 937–944 (2019).
Google Scholar
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).
Google Scholar
Verma, R., Mohl, D. & Deshaies, R. J. Harnessing the power of proteolysis for targeted protein inactivation. Mol. Cell 77, 446–460 (2020).
Google Scholar
Nalawansha, D. A. & Crews, C. M. PROTACs: an emerging therapeutic modality in precision medicine. Cell Chem. Biol. 27, 998–1014 (2020).
Google Scholar
Hanzl, A. & Winter, G. E. Targeted protein degradation: current and future challenges. Curr. Opin. Chem. Biol. 56, 35–41 (2020).
Google Scholar
Faust, T. B., Donovan, K. A., Yue, H., Chamberlain, P. P. & Fischer, E. S. Small-molecule approaches to targeted protein degradation. Annu. Rev. Cancer Biol. 5, 181–201 (2021).
Ciechanover, A., Orian, A. & Schwartz, A. L. Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays 22, 442–451 (2000).
Google Scholar
Burslem, G. M. & Crews, C. M. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell 181, 102–114 (2020).
Google Scholar
Ma, Y. et al. Targeted degradation of KRAS by an engineered ubiquitin ligase suppresses pancreatic cancer cell growth in vitro and in vivo. Mol. Cancer Ther. 12, 286–294 (2013).
Google Scholar
Hatakeyama, S., Watanabe, M., Fujii, Y. & Nakayama, K. I. Targeted destruction of c-Myc by an engineered ubiquitin ligase suppresses cell transformation and tumor formation. Cancer Res. 65, 7874–7879 (2005).
Google Scholar
Hon, W. C. et al. Structural basis for the recognition of hydroxyproline in HIF-1 alpha by pVHL. Nature 417, 975–978 (2002).
Google Scholar
Min, J. H. et al. Structure of an HIF-1alpha-pVHL complex: hydroxyproline recognition in signaling. Science 296, 1886–1889 (2002).
Google Scholar
Buckley, D. L. et al. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1alpha. Angew. Chem. Int. Ed. Engl. 51, 11463–11467 (2012).
Google Scholar
Buckley, D. L. et al. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1alpha interaction. J. Am. Chem. Soc. 134, 4465–4468 (2012).
Google Scholar
Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617 (2015).
Google Scholar
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).
Google Scholar
Gandhi, A. K. et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN). Br. J. Haematol. 164, 811–821 (2014).
Google Scholar
Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, eaal3755 (2017).
Google Scholar
Faust, T. B. et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 16, 7–14 (2020).
Google Scholar
Uehara, T. et al. Selective degradation of splicing factor CAPERalpha by anticancer sulfonamides. Nat. Chem. Biol. 13, 675–680 (2017).
Google Scholar
Du, X. et al. Structural basis and kinetic pathway of RBM39 recruitment to DCAF15 by a sulfonamide molecular glue E7820. Structure 27, 1625–1633 e1623 (2019).
Google Scholar
Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep. 29, 1499–1510 e1496 (2019).
Google Scholar
Mullard, A. Targeted protein degraders crowd into the clinic. Nat. Rev. Drug Discov. 20, 247–250 (2021).
Google Scholar
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).
Google Scholar
Chamberlain, P. P. et al. Evolution of cereblon-mediated protein degradation as a therapeutic modality. ACS Med. Chem. Lett. 10, 1592–1602 (2019).
Google Scholar
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).
Google Scholar
Neklesa, T. K., Winkler, J. D. & Crews, C. M. Targeted protein degradation by PROTACs. Pharmacol. Ther. 174, 138–144 (2017).
Google Scholar
Flanagan, J. J. & Neklesa, T. K. Targeting nuclear receptors with PROTAC degraders. Mol. Cell Endocrinol. 493, 110452 (2019).
Google Scholar
Sievers, Q. L. et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, eaat0572 (2018).
Google Scholar
Donovan, K. A. et al. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane radial ray syndrome. eLife 7, e38430 (2018).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
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).
Luh, L. M. et al. Prey for the proteasome: targeted protein degradation-a medicinal chemist’s perspective. Angew. Chem. Int. Ed. Engl. 59, 15448–15466 (2020).
Google Scholar
Samarasinghe, K. T. G. et al. Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras. Cell Chem. Biol. https://doi.org/10.1016/j.chembiol.2021.03.011 (2021).
Google Scholar
Farnaby, W., Koegl, M., McConnell, D. B. & Ciulli, A. Transforming targeted cancer therapy with PROTACs: A forward-looking perspective. Curr. Opin. Pharmacol. 57, 175–183 (2021).
Google Scholar
Hopkins, A. L. & Groom, C. R. The druggable genome. Nat. Rev. Drug Discov. 1, 727–730 (2002).
Google Scholar
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).
Google Scholar
Davis, C., Spaller, B. L. & Matouschek, A. Mechanisms of substrate recognition by the 26S proteasome. Curr. Opin. Struct. Biol. 67, 161–169 (2021).
Google Scholar
Mares, A. et al. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun. Biol. 3, 140 (2020).
Google Scholar
Bondeson, D. P. et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 25, 78–87 e75 (2018).
Google Scholar
Alabi, S. et al. Mutant-selective degradation by BRAF-targeting PROTACs. Nat. Commun. 12, 920 (2021).
Google Scholar
Farnaby, W. et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat. Chem. Biol. 15, 672–680 (2019).
Google Scholar
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).
Google Scholar
Nabet, B. et al. The dTAG system for immediate and target-specific protein degradation. Nat. Chem. Biol. 14, 431–441 (2018).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Ray, S. & Murkin, A. S. New electrophiles and strategies for mechanism-based and targeted covalent inhibitor design. Biochemistry 58, 5234–5244 (2019).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Shultz, M. D. Two decades under the influence of the rule of five and the changing properties of approved oral drugs. J. Med. Chem. 62, 1701–1714 (2019).
Google Scholar
Young, R. J. & Leeson, P. D. Mapping the efficiency and physicochemical trajectories of successful optimizations. J. Med. Chem. 61, 6421–6467 (2018).
Google Scholar
Scott, J. S. & Waring, M. J. Practical application of ligand efficiency metrics in lead optimisation. Bioorg. Med. Chem. 26, 3006–3015 (2018).
Google Scholar
Johnson, T. W., Gallego, R. A. & Edwards, M. P. Lipophilic efficiency as an important metric in drug design. J. Med. Chem. 61, 6401–6420 (2018).
Google Scholar
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).
Google Scholar
Poongavanam, V. & Kihlberg, J. PROTAC cell permeability and oral bioavailability: a journey into uncharted territory. Future Med. Chem. https://doi.org/10.4155/fmc-2021-0208 (2021).
Google Scholar
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).
Atilaw, Y. et al. Solution conformations shed light on PROTAC cell permeability. ACS Med. Chem. Lett. 12, 107–114 (2021).
Google Scholar
Cyrus, K. et al. Impact of linker length on the activity of PROTACs. Mol. Biosyst. 7, 359–364 (2011).
Google Scholar
Schneider, M. et al. The PROTACtable genome. Nat. Rev. Drug Discov. 20, 789–797 (2021).
Google Scholar
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).
Chamberlain, P. P. & Cathers, B. E. Cereblon modulators: low molecular weight inducers of protein degradation. Drug Discov. Today Technol. 31, 29–34 (2019).
Google Scholar
Matyskiela, M. E. et al. A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos. J. Med. Chem. 61, 535–542 (2018).
Google Scholar
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).
Google Scholar
Matyskiela, M. E. et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature 535, 252–257 (2016).
Google Scholar
Ege, N., Bouguenina, H., Tatari, M. & Chopra, R. Phenotypic screening with target identification and validation in the discovery and development of E3 ligase modulators. Cell Chem. Biol. 28, 283–299 (2021).
Google Scholar
He, Y. et al. DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas. J. Hematol. Oncol. 13, 95 (2020).
Google Scholar
Zhang, X. et al. Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-XL. Chem. Commun. 55, 14765–14768 (2019).
Google Scholar
Oh, E., Akopian, D. & Rape, M. Principles of ubiquitin-dependent signaling. Annu. Rev. Cell Dev. Biol. 34, 137–162 (2018).
Google Scholar
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).
Google Scholar
Fukuoka, K. et al. Mechanisms of action of the novel sulfonamide anticancer agent E7070 on cell cycle progression in human non-small cell lung cancer cells. Invest. New Drugs 19, 219–227 (2001).
Google Scholar
Owa, T. et al. Discovery of novel antitumor sulfonamides targeting G1 phase of the cell cycle. J. Med. Chem. 42, 3789–3799 (1999).
Google Scholar
Bussiere, D. E. et al. Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat. Chem. Biol. 16, 15–23 (2020).
Google Scholar
Lv, L. et al. Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. eLife 9, e59994 (2020).
Google Scholar
Slabicki, M. et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature 585, 293–297 (2020).
Google Scholar
Mayor-Ruiz, C. et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 16, 1199–1207 (2020).
Google Scholar
Dieter, S. M. et al. Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. Cell Rep. 36, 109394 (2021).
Google Scholar
Asatsuma-Okumura, T., Ito, T. & Handa, H. Molecular mechanisms of cereblon-based drugs. Pharmacol. Ther. 202, 132–139 (2019).
Google Scholar
Nguyen, K. M. & Busino, L. Targeting the E3 ubiquitin ligases DCAF15 and cereblon for cancer therapy. Semin. Cancer Biol. 67, 53–60 (2020).
Google Scholar
Fang, Y., Liao, G. & Yu, B. Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. Acta Pharm. Sin. B 10, 1253–1278 (2020).
Google Scholar
Naito, M., Ohoka, N., Shibata, N. & Tsukumo, Y. Targeted protein degradation by chimeric small molecules, PROTACs and SNIPERs. Front. Chem. 7, 849 (2019).
Google Scholar
Weng, G. et al. PROTAC-DB: an online database of PROTACs. Nucleic Acids Res. 49, D1381–D1387 (2021).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Nabet, B. et al. Rapid and direct control of target protein levels with VHL-recruiting dTAG molecules. Nat. Commun. 11, 4687 (2020).
Google Scholar
Roth, S., Fulcher, L. J. & Sapkota, G. P. Advances in targeted degradation of endogenous proteins. Cell Mol. Life Sci. 76, 2761–2777 (2019).
Google Scholar
Prozzillo, Y. et al. Targeted protein degradation tools: overview and future perspectives. Biology (Basel) 9, 421 (2020).
Google Scholar
Pacini, C. et al. Integrated cross-study datasets of genetic dependencies in cancer. Nat. Commun. 12, 1661 (2021).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Zimmerman, E. S., Schulman, B. A. & Zheng, N. Structural assembly of cullin-RING ubiquitin ligase complexes. Curr. Opin. Struct. Biol. 20, 714–721 (2010).
Google Scholar
Duda, D. M. et al. Structural regulation of cullin-RING ubiquitin ligase complexes. Curr. Opin. Struct. Biol. 21, 257–264 (2011).
Google Scholar
Baek, K. et al. NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly. Nature 578, 461–466 (2020).
Google Scholar
Baek, K., Scott, D. C. & Schulman, B. A. NEDD8 and ubiquitin ligation by cullin-RING E3 ligases. Curr. Opin. Struct. Biol. 67, 101–109 (2020).
Google Scholar
Yau, R. & Rape, M. The increasing complexity of the ubiquitin code. Nat. Cell Biol. 18, 579–586 (2016).
Google Scholar
Komander, D. & Rape, M. The ubiquitin code. Annu. Rev. Biochem. 81, 203–229 (2012).
Google Scholar
Zheng, N. & Shabek, N. Ubiquitin ligases: structure, function, and regulation. Annu. Rev. Biochem. 86, 129–157 (2017).
Google Scholar
Liu, L. et al. UbiHub: a data hub for the explorers of ubiquitination pathways. Bioinformatics 35, 2882–2884 (2019).
Google Scholar
Zhang, W. et al. System-wide modulation of HECT E3 ligases with selective ubiquitin variant probes. Mol. Cell 62, 121–136 (2016).
Google Scholar
Kamadurai, H. B. et al. Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3. eLife 2, e00828 (2013).
Google Scholar
Yuan, L., Lv, Z., Atkison, J. H. & Olsen, S. K. Structural insights into the mechanism and E2 specificity of the RBR E3 ubiquitin ligase HHARI. Nat. Commun. 8, 211 (2017).
Google Scholar
Dove, K. K. et al. Structural studies of HHARI/UbcH7~Ub reveal unique E2~Ub conformational restriction by RBR RING1. Structure 25, 890–900 e895 (2017).
Google Scholar
Scott, D. C. et al. Two distinct types of E3 ligases work in unison to regulate substrate ubiquitylation. Cell 166, 1198–1214 e1124 (2016).
Google Scholar
Horn-Ghetko, D. et al. Ubiquitin ligation to F-box protein targets by SCF-RBR E3-E3 super-assembly. Nature 590, 671–676 (2021).
Google Scholar
Lai, A. C. et al. Modular PROTAC design for the degradation of oncogenic BCR-ABL. Angew. Chem. Int. Ed. Engl. 55, 807–810 (2016).
Google Scholar
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).
Google Scholar
Janes, M. R. et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell 172, 578–589 e517 (2018).
Google Scholar
Moore, A. R., Rosenberg, S. C., McCormick, F. & Malek, S. RAS-targeted therapies: is the undruggable drugged? Nat. Rev. Drug Discov. 19, 533–552 (2020).
Google Scholar
Hallin, J. et al. The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10, 54–71 (2020).
Google Scholar
Canon, J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019).
Google Scholar
Zeng, M. et al. Exploring targeted degradation strategy for oncogenic KRAS(G12C). Cell Chem. Biol. 27, 19–31 e16 (2020).
Google Scholar
Huang, H. T. et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem. Biol. 25, 88–99 e86 (2018).
Google Scholar
Donovan, K. A. et al. Mapping the degradable kinome provides a resource for expedited degrader development. Cell 183, 1714–1731 e1710 (2020).
Google Scholar
Rodriguez-Rivera, F. P. & Levi, S. M. Unifying catalysis framework to dissect proteasomal degradation paradigms. ACS Cent. Sci. 7, 1117–1125 (2021).
Google Scholar
Hughes, S. J. & Ciulli, A. Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. Essays Biochem. 61, 505–516 (2017).
Google Scholar
Gadd, M. S. et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13, 514–521 (2017).
Google Scholar
Nowak, R. P. et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14, 706–714 (2018).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Spradlin, J. N. et al. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat. Chem. Biol. 15, 747–755 (2019).
Google Scholar
Luo, M. et al. Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function. Cell Chem. Biol. 28, 559–566 (2021).
Google Scholar
Tong, B. et al. A nimbolide-based kinase degrader preferentially degrades oncogenic BCR-ABL. ACS Chem. Biol. 15, 1788–1794 (2020).
Google Scholar
Tong, B. et al. Bardoxolone conjugation enables targeted protein degradation of BRD4. Sci. Rep. 10, 15543 (2020).
Google Scholar
Wei, J. et al. Harnessing the E3 Ligase KEAP1 for targeted protein degradation. J. Am. Chem. Soc. 143, 15073–15083 (2021).
Google Scholar
Henning, N. J. et al. Discovery of a covalent FEM1B recruiter for targeted protein degradation applications. bioRxiv https://doi.org/10.1101/2021.04.15.439993 (2021).
Google Scholar
Ishida, T. & Ciulli, A. E3 ligase ligands for PROTACs: how they were found and how to discover new ones. SLAS Discov. 26, 484–502 (2021).
Google Scholar
Ramachandran, S. & Ciulli, A. Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues. Curr. Opin. Struct. Biol. 67, 110–119 (2020).
Google Scholar
Tunyasuvunakool, K. et al. Highly accurate protein structure prediction for the human proteome. Nature 596, 590–596 (2021).
Google Scholar
Baek, M. et al. Accurate prediction of protein structures and interactions using a three-track neural network. Science 373, 871–876 (2021).
Google Scholar
Khan, S. et al. PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics. Oncogene 39, 4909–4924 (2020).
Google Scholar
He, Y. et al. Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies. J. Hematol. Oncol. 13, 103 (2020).
Google Scholar
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).
Google Scholar
Gupta, V. A. et al. Identification of KLHL41 mutations implicates BTB-kelch-mediated ubiquitination as an alternate pathway to myofibrillar disruption in nemaline myopathy. Am. J. Hum. Genet. 93, 1108–1117 (2013).
Google Scholar
Garg, A. et al. KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy. J. Clin. Invest. 124, 3529–3539 (2014).
Google Scholar
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).
Google Scholar
Menon, S. et al. The TRIM9/TRIM67 neuronal interactome reveals novel activators of morphogenesis. Mol. Biol. Cell 32, 314–330 (2021).
Google Scholar
Kumanomidou, T. et al. The structural differences between a glycoprotein specific F-box protein Fbs1 and its homologous protein FBG3. PLoS ONE 10, e0140366 (2015).
Google Scholar
Glenn, K. A., Nelson, R. F., Wen, H. M., Mallinger, A. J. & Paulson, H. L. Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases. J. Biol. Chem. 283, 12717–12729 (2008).
Google Scholar
Khan, S. et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 25, 1938–1947 (2019).
Google Scholar
Zhang, X. et al. Discovery of PROTAC BCL-XL degraders as potent anticancer agents with low on-target platelet toxicity. Eur. J. Med. Chem. 192, 112186 (2020).
Google Scholar
Wei, R. et al. Cancer testis antigens in sarcoma: expression, function and immunotherapeutic application. Cancer Lett. 479, 54–60 (2020).
Google Scholar
Weon, J. L. & Potts, P. R. The MAGE protein family and cancer. Curr. Opin. Cell Biol. 37, 1–8 (2015).
Google Scholar
Yang, S. W. et al. A cancer-specific ubiquitin ligase drives mRNA alternative polyadenylation by ubiquitinating the mRNA 3′ end processing complex. Mol. Cell 77, 1206–1221 e1207 (2020).
Google Scholar
Pineda, C. T. et al. Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell 160, 715–728 (2015).
Google Scholar
Lee, A. K. & Potts, P. R. A comprehensive guide to the MAGE family of ubiquitin ligases. J. Mol. Biol. 429, 1114–1142 (2017).
Google Scholar
Tacer, K. F. & Potts, P. R. Cellular and disease functions of the Prader-Willi syndrome gene MAGEL2. Biochem. J. 474, 2177–2190 (2017).
Google Scholar
Pillow, T. H. et al. Antibody conjugation of a chimeric BET degrader enables in vivo activity. ChemMedChem 15, 17–25 (2020).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Dobrovolsky, D. et al. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer. Blood 133, 952–961 (2019).
Google Scholar
Zarrin, A. A., Bao, K., Lupardus, P. & Vucic, D. Kinase inhibition in autoimmunity and inflammation. Nat. Rev. Drug Discov. 20, 39–63 (2021).
Google Scholar
Schiemer, J. et al. Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes. Nat. Chem. Biol. 17, 152–160 (2021).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Wiese, M. D., Manning-Bennett, A. T. & Abuhelwa, A. Y. Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis. Expert Opin. Investig. Drugs 29, 475–482 (2020).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Nunes, J. et al. Targeting IRAK4 for degradation with PROTACs. ACS Med. Chem. Lett. 10, 1081–1085 (2019).
Google Scholar
Chen, Y. et al. Design, synthesis, and biological evaluation of IRAK4-targeting PROTACs. ACS Med. Chem. Lett. 12, 82–87 (2021).
Google Scholar
van der Zanden, S. Y., Luimstra, J. J., Neefjes, J., Borst, J. & Ovaa, H. Opportunities for small molecules in cancer immunotherapy. Trends Immunol. 41, 493–511 (2020).
Google Scholar
Kerr, W. G. & Chisholm, J. D. The next generation of immunotherapy for cancer: small molecules could make big waves. J. Immunol. 202, 11–19 (2019).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Wang, Y. & Mandelkow, E. Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 5–21 (2016).
Google Scholar
Goedert, M. Tau protein and neurodegeneration. Semin. Cell Dev. Biol. 15, 45–49 (2004).
Google Scholar
Chang, C. W., Shao, E. & Mucke, L. Tau: enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies. Science 371, eabb8255 (2021).
Google Scholar
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).
Google Scholar
Yiannopoulou, K. G. & Papageorgiou, S. G. Current and future treatments in Alzheimer disease: an update. J. Cent. Nerv. Syst. Dis. 12, 1179573520907397 (2020).
Google Scholar
Wegmann, S. et al. Persistent repression of tau in the brain using engineered zinc finger protein transcription factors. Sci. Adv. 7, eabe1611 (2021).
Google Scholar
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).
Google Scholar
Wang, W. et al. A novel small-molecule PROTAC selectively promotes tau clearance to improve cognitive functions in Alzheimer-like models. Theranostics 11, 5279–5295 (2021).
Google Scholar
Chien, D. T. et al. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J. Alzheimers Dis. 34, 457–468 (2013).
Google Scholar
Silva, M. C. et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. eLife 8, e45457 (2019).
Google Scholar
Kotzbauer, P. T., Trojanowsk, J. Q. & Lee, V. M. Lewy body pathology in Alzheimer’s disease. J. Mol. Neurosci. 17, 225–232 (2001).
Google Scholar
Qu, J. et al. Specific knockdown of alpha-synuclein by peptide-directed proteasome degradation rescued its associated neurotoxicity. Cell Chem. Biol. 27, 763 (2020).
Google Scholar
MacDonald, M. E. et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983 (1993).
Sap, K. A. & Reits, E. A. Strategies to investigate ubiquitination in Huntington’s disease. Front. Chem. 8, 485 (2020).
Google Scholar
Li, Z. et al. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 575, 203–209 (2019).
Google Scholar
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).
Google Scholar
de Wispelaere, M. et al. Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations. Nat. Commun. 10, 3468 (2019).
Google Scholar
Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020).
Google Scholar
Martinez-Ortiz, W. & Zhou, M. M. Could PROTACs protect us from COVID-19? Drug Discov. Today 25, 1894–1896 (2020).
Google Scholar
Ghosh, A. K., Brindisi, M., Shahabi, D., Chapman, M. E. & Mesecar, A. D. Drug development and medicinal chemistry efforts toward SARS-coronavirus and Covid-19 therapeutics. ChemMedChem 15, 907–932 (2020).
Google Scholar
Yin, W. et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science 368, 1499–1504 (2020).
Google Scholar
Boras, B. et al. Discovery of a novel inhibitor of coronavirus 3CL protease as a clinical candidate for the potential treatment of COVID-19. bioRxiv https://doi.org/10.1101/2020.09.12.293498 (2020).
Google Scholar
De Haan, P., Van Diemen, F. R. & Toscano, M. G. Viral gene delivery vectors: the next generation medicines for immune-related diseases. Hum. Vaccin. Immunother. 17, 14–21 (2021).
Google Scholar
Sung, Y. K. & Kim, S. W. Recent advances in the development of gene delivery systems. Biomater. Res. 23, 8 (2019).
Google Scholar
Ghosh, S., Brown, A. M., Jenkins, C. & Campbell, K. Viral vector systems for gene therapy: a comprehensive literature review of progress and biosafety challenges. Appl. Biosaf. 25, 7–18 (2020).
Yang, K. C. et al. Nanotechnology advances in pathogen- and host-targeted antiviral delivery: multipronged therapeutic intervention for pandemic control. Drug Deliv. Transl. Res. 11, 1420–1437 (2021).
Google Scholar
Steinhauff, D. & Ghandehari, H. Matrix mediated viral gene delivery: a review. Bioconjug Chem. 30, 384–399 (2019).
Google Scholar
Editorial. Let’s talk about lipid nanoparticles. Nat. Rev. Mater. 6, 99 (2021).
Zhou, P., Bogacki, R., McReynolds, L. & Howley, P. M. Harnessing the ubiquitination machinery to target the degradation of specific cellular proteins. Mol. Cell 6, 751–756 (2000).
Google Scholar
Li, X. et al. Degradation of HER2 by Cbl-based chimeric ubiquitin ligases. Cancer Res. 67, 8716–8724 (2007).
Google Scholar
Pan, T. et al. A recombinant chimeric protein specifically induces mutant KRAS degradation and potently inhibits pancreatic tumor growth. Oncotarget 7, 44299–44309 (2016).
Google Scholar
Chu, T. T. et al. Specific knockdown of endogenous tau protein by peptide-directed ubiquitin-proteasome degradation. Cell Chem. Biol. 23, 453–461 (2016).
Google Scholar
Lim, S. et al. bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA). Proc. Natl Acad. Sci. USA 117, 5791–5800 (2020).
Google Scholar
Fulcher, L. J. et al. An affinity-directed protein missile system for targeted proteolysis. Open Biol. 6, 160255 (2016).
Google Scholar
Saerens, D. et al. Identification of a universal VHH framework to graft non-canonical antigen-binding loops of camel single-domain antibodies. J. Mol. Biol. 352, 597–607 (2005).
Google Scholar
Caussinus, E., Kanca, O. & Affolter, M. Fluorescent fusion protein knockout mediated by anti-GFP nanobody. Nat. Struct. Mol. Biol. 19, 117–121 (2011).
Google Scholar
Shin, Y. J. et al. Nanobody-targeted E3-ubiquitin ligase complex degrades nuclear proteins. Sci. Rep. 5, 14269 (2015).
Google Scholar
Lim, S. et al. Exquisitely specific anti-KRAS biodegraders inform on the cellular prevalence of nucleotide-loaded states. ACS Cent. Sci. 7, 274–291 (2021).
Google Scholar
Ghidini, A., Clery, A., Halloy, F., Allain, F. H. T. & Hall, J. RNA-PROTACs: Degraders of RNA-binding proteins. Angew. Chem. Int. Ed. Engl. 60, 3163–3169 (2021).
Google Scholar
Shao, J. et al. Destruction of DNA-binding proteins by programmable O’PROTAC: oligonucleotide-based PROTAC. bioRxiv https://doi.org/10.1101/2021.03.08.434493 (2021).
Google Scholar
Liu, J. et al. TF-PROTACs enable targeted degradation of transcription factors. J. Am. Chem. Soc. 143, 8902–8910 (2021).
Google Scholar
Angers, S. et al. Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 443, 590–593 (2006).
Google Scholar
Page, R. C. P., Amick, J. J. N., Klevit, R. E. & Misra, S. Structural Insights into the conformation and oligomerization of E2∼ubiquitin conjugates. Biochemistry 51, 4175–4187 (2012).
Google Scholar
Faull, S. V. et al. Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome. Nat. Commun. 10, 3814 (2019).
Google Scholar
Zhang, M. et al. Chaperoned ubiquitylation–crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex. Mol. Cell 20, 525–538 (2005).
Google Scholar
Kiss, L. et al. A tri-ionic anchor mechanism drives Ube2N-specific recruitment and K63-chain ubiquitination in TRIM ligases. Nat. Commun. 10, 4502 (2019).
Google Scholar
Kannt, A. & Dikic, I. Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation. Cell Chem. Biol. 28, 1014–1031 (2021).
Google Scholar
Jevtic, P., Haakonsen, D. L. & Rape, M. An E3 ligase guide to the galaxy of small-molecule-induced protein degradation. Cell Chem. Biol. 28, 1000–1013 (2021).
Google Scholar
Chen, Y. N. et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 535, 148–152 (2016).
Google Scholar
Liu, J. et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66, 807–815 (1991).
Google Scholar
Schreiber, S. L. The rise of molecular glues. Cell 184, 3–9 (2021).
Google Scholar
Deshaies, R. J. Multispecific drugs herald a new era of biopharmaceutical innovation. Nature 580, 329–338 (2020).
Google Scholar
Simonetta, K. R. et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat. Commun. 10, 1402 (2019).
Google Scholar
Koduri, V. et al. Targeting oncoproteins with a positive selection assay for protein degraders. Sci. Adv. 7, eabd6263 (2021).
Google Scholar
Lou, Z. & Wang, S. E3 ubiquitin ligases and human papillomavirus-induced carcinogenesis. J. Int. Med. Res. 42, 247–260 (2014).
Google Scholar
Planelles, V. & Barker, E. Roles of Vpr and Vpx in modulating the virus-host cell relationship. Mol. Asp. Med. 31, 398–406 (2010).
Google Scholar
Yan, J. et al. HIV-1 Vpr reprograms CLR4(DCAF1) E3 ubiquitin ligase to antagonize exonuclease 1-mediated restriction of HIV-1 infection. mBio 9, e01732-18 (2018).
Google Scholar
Dharmasiri, N., Dharmasiri, S. & Estelle, M. The F-box protein TIR1 is an auxin receptor. Nature 435, 441–445 (2005).
Google Scholar
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).
Google Scholar
Thines, B. et al. JAZ repressor proteins are targets of the SCF(COI1) complex during jasmonate signalling. Nature 448, 661–665 (2007).
Google Scholar
Larrieu, A. & Vernoux, T. Comparison of plant hormone signalling systems. Essays Biochem. 58, 165–181 (2015).
Google Scholar
Guo, Y. et al. Structural basis for hijacking CBF-beta and CUL5 E3 ligase complex by HIV-1 Vif. Nature 505, 229–233 (2014).
Google Scholar
Wu, Y. et al. The DDB1-DCAF1-Vpr-UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction. Nat. Struct. Mol. Biol. 23, 933–940 (2016).
Google Scholar
Martinez-Zapien, D. et al. Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 529, 541–545 (2016).
Google Scholar
Ding, Y., Fei, Y. & Lu, B. Emerging new concepts of degrader technologies. Trends Pharmacol. Sci. 41, 464–474 (2020).
Google Scholar
Kastl, J. M., Davies, G., Godsman, E. & Holdgate, G. A. Small-molecule degraders beyond PROTACs-challenges and opportunities. SLAS Discov. 26, 524–533 (2021).
Google Scholar
Alabi, S. & Crews, C. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. J. Biol. Chem. 296, 100647 (2021).
Google Scholar
Takahashi, D. et al. AUTACs: cargo-specific degraders using selective autophagy. Mol. Cell 76, 797–810 e710 (2019).
Google Scholar
Banik, S. M. et al. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 584, 291–297 (2020).
Google Scholar
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).
Google Scholar
