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

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.