Bispecific Estrogen Receptor α Degraders Incorporating Novel Binders Identified Using DNA-Encoded Chemical Library Screening.

Autor:	Disch JS; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Duffy JM; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Lee ECY; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Gikunju D; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Chan B; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Levin B; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Monteiro MI; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Talcott SA; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Lau AC; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Zhou F; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Kozhushnyan A; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Westlund NE; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Mullins PB; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Yu Y; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., von Rechenberg M; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Zhang J; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Arnautova YA; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Liu Y; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Zhang Y; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., McRiner AJ; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Keefe AD; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Kohlmann A; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Clark MA; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Cuozzo JW; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Huguet C; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States., Arora S; X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Apr 22; Vol. 64 (8), pp. 5049-5066. Date of Electronic Publication: 2021 Apr 12.
DOI:	10.1021/acs.jmedchem.1c00127
Abstrakt:	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.
Databáze:	MEDLINE
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