Bispecific Estrogen Receptor A Degraders Incorporating Novel Binders Identified Using Dna-Encoded Chemical Library Screening

Bispecific degraders (PROTACs) of ER alpha are expected to be advantageous over current inhibitors of ER alpha 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 similar to 120 billion DNA-encoded molecules with ER alpha WT and 3 gain-of-function (GOF) mutants, with and without estradiol to identify features that enrich ER alpha competitively, the off-DNA synthesized small molecule exemplar 7 exhibited nanomolar ER alpha 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 ER alpha, 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.