Abstract
Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing a privileged rewiring of cellular biochemistry. While rational design strategies can expedite the discovery of heterobifunctional CIPs, molecular glues have predominantly been discovered by serendipity. Envisioning a prospective approach to discover molecular glues for a pre-selected target, we hypothesized that pre-existing ligands could be systematically decorated with chemical modifications to discover protein-ligand surfaces that are tuned to cooperatively engage another protein interface. Using high-throughput chemical synthesis to diversify a ligand for the transcriptional coactivator ENL with 3,163 structurally diverse chemical building blocks, we discovered a compound dHTC1 that elicits potent, selective, and stereochemistry-dependent degradation of ENL by induced binding to CRL4CRBN. Unlike prior CRBN-based degraders, dHTC1 binds the ligase with high affinity only after forming the ENL:dHTC1 complex, relying on a hybrid interface of protein-protein and protein-ligand contacts. Altogether, this study points toward an expanded chemical space for co-opting the therapeutically important substrate receptor, CRBN, and a second proof-of-concept extending this approach to BRD4 further validates high-throughput chemistry as a facile tool to discover new degraders.
Competing Interest Statement
M.A.E. and S.K. are inventors on a patent application related to SR-0813 and TM-7. M.A.E. and J.B.S. are inventors on a patent application related to dHTC1. M.A.E holds equity in Nexo Therapeutics and serves on their scientific advisory board. G.E.W. is a scientific founder and shareholder of Proxygen and Solgate and on the Scientific Advisory Board of Nexo Therapeutics. The Winter lab has received research funding from Pfizer. E.S.F. is a founder, scientific advisory board (SAB) member, and equity holder of Civetta Therapeutics, Proximity Therapeutics, Stelexis Biosciences, and Neomorph, Inc. (also board of directors). He is an equity holder and SAB member for Avilar Therapeutics, Photys Therapeutics, and Ajax Therapeutics and an equity holder in Lighthorse Therapeutics, CPD4, Inc and Anvia Therapeutics. E.S.F. is a consultant to Novartis, EcoR1 capital, Odyssey and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, Bayer and Astellas. A.C. is co-founder and shareholder of Amphista Therapeutics, a company that develops targeted protein degradation platforms. The Ciulli laboratory receives or has received sponsored research support from Almirall, Amgen, Amphista Therapeutics, Boehringer Ingelheim, Eisai, Merck KgaA, Nurix Therapeutics, Ono Pharmaceutical and Tocris-Biotechne. B.F.C. and B.M. are founders and/or scientific advisors to Magnet Biomedicine.