Covalent ER alpha Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant for Breast Cancer

Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ER alpha) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ER alpha antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ER alpha(WT)) and mutant ER alpha (ER alpha(MUT)). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both ER alpha(W)(T/MUT), and maintains potency even in the context of ER alpha C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ER alpha(WT) and ER alpha(MUT) palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy-resistant ER alpha(+) breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). Summary: H3B-6545 is an ER alpha covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naive and resistant ER alpha(WT) and ER alpha(MUT) tumors.