Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity

• DOI: 10.26434/chemrxiv-2021-7lbk4-v2
• Publication Date: 2022-02-01T13:48:34Z
• Authors: Satomi Imaide; Kristin M. Riching; Nikolai Makukhin; Vesna Vetma; Claire Whitworth; Scott J. Hughes; Nicole Trainor; Sarah D. Mahan; Nancy Murphy; Angus Cowan; Kwok-Ho Chan; Conner Craigon; Andrea Testa; Chiara Maniaci; Marjeta Urh; Danette L. Daniels; Alessio Ciulli
• Keywords: Cooperativity; Ternary complex; Avidity; Cooperative binding; Bivalent (engine); Linker; Ligand efficiency

Bivalent PROTACs work drive protein degradation by simultaneously binding a target and an E3 ligase forming productive ternary complex. We hypothesized that increasing valency within PROTAC could enhanced degradation. Here, we designed trivalent consisting of bivalent BET inhibitor ligand, tethered via branched linker. identified VHL-based SIM1 as low picomolar degrader, with preference for BRD2. Compared to PROTACs, showed more sustained higher efficacy, which led potent anti-cancer activity. Mechanistically, engages high avidity both bromodomains in cis intramolecular fashion forms 1:1:1 complex VHL exhibiting positive cooperativity cellular stability prolonged residence time. Collectively, our data along favorable vivo pharmacokinetics demonstrate augmenting the proximity-induced modalities can be enabling strategy advancing functional outcomes.