Advances in Targeted Therapy: The Emergence of H3B-6545 in Breast Cancer Treatment

Estrogen receptor (ER) mutations are found in a significant portion of patients who initially respond to anti-endocrine treatments but later experience a relapse. These mutations can lead to resistance against the current endocrine therapies, which are less effective against ERα mutations. A new series of compounds, known as Selective Estrogen Receptor Covalent Antagonists (SERCAs), have been developed to target both wild-type and mutant ERα by inactivating the receptor through a unique mechanism. This approach focuses on a specific cysteine residue not found in other nuclear hormone receptors, resulting in a distinct biological profile compared to Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs).

A candidate from this series, H3B-6545, has been identified through structure-based drug design as a highly selective molecule with potent antagonizing effects on both wild-type and mutant ERα. It has demonstrated increased cell potency in vitro, both under continuous and washout treatment conditions, and has shown superior efficacy to fulvestrant in the MCF-7 xenograft model at doses significantly lower than the maximum tolerated dose in mice. H3B-6545 also outperforms tamoxifen and fulvestrant in patient-derived xenograft models of estrogen receptor-positive breast cancer, including those with ERα mutations.

In non-clinical safety studies, H3B-6545 has been well-tolerated in rats and monkeys at a wide range of doses and exposures that surpass the levels needed for efficacy in mouse xenograft models. This first-in-class, orally available compound presents a promising preclinical profile for the treatment of breast cancer, with both efficacy and safety demonstrated.

The research was presented at the American Association for Cancer Research Annual Meeting in 2017, with the citation highlighting the discovery and development of H3B-6545 as a novel oral SERCA for breast cancer treatment.