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

Breast cancer is the most common cancer in women, accounting for 15% of all cancer-related deaths. ERα, one of the main subtypes of estrogen receptors, overexpressed in ~70% of all breast cancers, is responsible for the cancer cell proliferation, survival, and metastasis. Although there are several existing endocrine therapies and second generation SERDs for breast cancer management, they have been fraught with liabilities including poor PK and development of acquired resistance. Hence there is an urgent need to develop next generation ERα-targeted therapeutics, targeting both WT and GOF mutations (involving amino acids Y537 and D538), to hamper aggressive disease progression and improve overall survival rate.

The novel drug discovery and development platform, PROTAC (proteolysis targeting chimera), has shown promising therapeutic strategy, utilizing bifunctional degraders for successful degradation of ERα, using well known binders. However, this platform has also been faced with challenges for optimal linker presentation, use of novel POI and ubiquitin ligase binders, thus affecting its optimal design. DNA-encoded chemical libraries (DEL), that utilizes tethered molecules, may serve as the best option for identifying novel ligands suitable for ERα-PROTACS.

Herein, we report the discovery of a series of novel highly potent ERα bispecific degraders (PROTACs), with nanomolar DC50 values, that target both WT and mutant ERα, without any off target activity in ER-negative or normal immortalized breast cells, using DEL screening. Utilizing our initially discovered, novel highly potent ERα binders and antagonists, we developed novel POI engagers for generating bi-functional ERα degraders. Further validation using VHL ligand as a competitor, and a negative control PROTAC, incorporating an inactive stereoisomer in the VHL-binding portion, revealed mechanism based activity. The VHL-phenoxy variant, was also found to be efficacious in ERα-dependent mouse xenograft model, showing significant tumor shrinkage, consistent with the PK/PD data. Thus these compounds identified through DEL screening, serve as valuable tools to advance the novel ERα-based PROTACS for breast cancer.