Discovery and development of a novel PI3K-CDK4/6 dual inhibitor PC-13 for the treatment of breast cancer

Breast cancer continues to be a major cause of cancer-associated mortality globally, underscoring the urgent need for innovative therapeutic strategies. In this study, we report the discovery and preclinical characterization of PC-13, a potential first-in-class dual inhibitor targeting both PI3K and CDK4/6. PC-13 demonstrates nanomolar-level potency against PI3K and CDK4/6 kinases, high selectivity across a broad panel of kinases, and potent antiproliferative effects in multiple breast cancer cell lines. Furthermore, PC-13 exhibits reasonable pharmacokinetic properties and achieves significant tumor growth suppression in a T47D xenograft model, with efficacy comparable to the Palbociclib-Buparlisib combination regimen, while maintaining a promising safety profile. Our findings highlight the potential of concurrent PI3K and CDK4/6 inhibition as a novel and effective therapeutic approach for breast cancer, supporting further development of PC-13 as a clinical candidate.