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Enhancing Intracellular Accumulation and Target Engagement of PROTACs with Reversible Covalent Chemistry

By Wen-Hao Guo, Xiaoli Qi, Xin Yu, Yang Liu, Chan-I Chung, Fang Bai, Xingcheng Lin, Dong Lu, Lingfei Wang, Jianwei Chen, Lynn Hsiao Su, Krystle J. Nomie, Feng Li, Meng C. Wang, Xiaokun Shu, José N. Onuchic, Jennifer A. Woyach, Michael L. Wang, Jin Wang

Posted 30 Dec 2019
bioRxiv DOI: 10.1101/2019.12.30.873588 (published DOI: 10.1038/s41467-020-17997-6)

Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton’s Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy. ### Competing Interest Statement J.W., W.G., X.Q., M.L.W., K.N., and Y.L. are the co-inventors of a patent related to this work. J.W. is the co-founder of CoActigon Inc. and Chemical Biology Probes LLC. X.S. and C.-I.C. have filed a patent application covering the SPPIER assay. M.L.W. receives research grants from Janssen, Pharmacyclics, AstraZeneca, Acerta Pharma, Celgene, Juno Therapeutics, BeiGene, Kite Pharma, Loxo Oncology, VelosBio, BioInvent, Aviara, Verastem, and InnoCare, consults and/or serves on the advisory board for Consulting/Advisory Board for Loxo Oncology, Janssen, Pharmacyclics, BioInvent, Celgene, Juno Therapeutics, Pulse Biosciences, MoreHealth, Guidepoint Global, Kite Pharma, AstraZeneca, Acerta Pharma, and InnoCare, received honoraria from Janssen, Acerta Pharma, OMI, Physicians Education Resources (PER), Oncology News, and Targeted Oncology, and owns stocks from MoreHealth. J.A.W. consults for Janssen, Pharmacyclics, Abbvie, AstraZeneca, and Arqule, receives research funding from Loxo Oncology and Abbvie and clinical trial funding from Pharmacyclics, Janssen, Verastem, Karyopharm, and Morphosys.

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