Jeremy S. Disch; Jennifer M. Duffy; Esther C. Y. Lee; Diana Gikunju; Betty Chan; Benjamin Levin; Michael I. Monteiro; Sarah A. Talcott; Anthony C. Lau; Fei Zhou; Anton Kozhushnyan; Neil E. Westlund; Patrick B. Mullins; Yan Yu; Moritz von Rechenberg; Junyi Zhang; Yelena A. Arnautova; Yanbin Liu; Ying Zhang; Andrew J. McRiner; Anthony D. Keefe; Anna Kohlmann; Matthew A. Clark; John W. Cuozzo; Christelle Huguet; Shilpi Arora
J. Med. Chem., 2021, 64(8), 5049–5066
https://doi.org/10.1021/acs.jmedchem.1c00127

Abstract

Bispecific degraders (PROTACs) of ERα are expected to be advantageous over current inhibitors of ERα signaling (aromatase inhibitors/SERMs/SERDs) used to treat ER+ breast cancer. Information from DNA-encoded chemical library (DECL) screening provides a method to identify novel PROTAC binding features as the linker positioning, and binding elements are determined directly from the screen. After screening ∼120 billion DNA-encoded molecules with ERα WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ERα competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ERα binding, antagonism, and degradation. Click chemistry synthesis on an alkyne E3 ligase engagers panel and an azide variant of 7 rapidly generated bispecific nanomolar degraders of ERα, with PROTACs 18 and 21 inhibiting ER+ MCF7 tumor growth in a mouse xenograft model of breast cancer. This study validates this approach toward identifying novel bispecific degrader leads from DECL screening with minimal optimization.