posted on 2021-04-12, 20:29authored byJeremy 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
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.