ICE Bioscience Posters

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Breast cancer remains a leading cause of cancer-related mortality worldwide. While the simultaneous inhibition of PI3Kα and CDK4/6 has recently been clinically validated for advanced breast cancer, combination regimens of distinct targeted agents are often limited by overlapping toxicities and complex pharmacokinetics. To address these clinical hurdles and overcome therapeutic resistance, we developed a novel series of single-molecule dual PI3K/CDK4- 6 inhibitors by structure-based drug design strategy. Through extensive SAR studies, lead compounds 11 and 13 were identified, exhibiting nanomolar potency against PI3Kα and CDK4/6, high kinase selectivity, and potent antiproliferative activity in breast cancer cell lines. Compound 13 demonstrated robust in vivo efficacy in a T47D xenograft model, comparable to the Palbociclib–BKM120 combination with a good safety profile. This work highlights single- molecule dual PI3K/CDK4-6 inhibition as a highly promising therapeutic strategy for breast cancer.