Koen F. W. Hekking; Sergio Maroto; Kees van Kekem; Frank S. Haasjes; Jack C. Slootweg; Patrick G. B. Oude Alink; Ron Dirks; Malvika Sardana; Marjon G. Bolster; Brian Kuijpers; Dennis Smith; Robin Doodeman; Marcel Scheepstra; Birgit Zech; Mark Mulvihill; Louis M. Renzetti; Lee Babiss; Paolo A. Centrella; Matthew A. Clark; John W. Cuozzo; Marie-Aude Guié; Eric Sigel; Sevan Habeshian; Christopher D. Hupp; Julie Liu; Heather A. Thomson; Ying Zhang; Anthony D. Keefe; Gerhard Müller; Stijn Gremmen
J. Med. Chem., 2024, XXXX, XXX, XXX-XXX
https://doi.org/10.1021/acs.jmedchem.3c02206

Abstract

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.