In this study, we describe the first in class rationally-designed triple activity inhibitor that concomitantly disrupts functions of three critical targets based upon known synthetic lethality relationships in cancer cells-CDK4/6, PI3K, and BRD4.The triple inhibitor SRX3177 has broad cytotoxic activity against a variety of tumor types.Our results using a cyclin D1-dependent hematol. malignancy, a MYC-dependent embryonal tumor, and a PI3K-dependent solid tumor demonstrate that SRX3177 is efficacious and non-toxic in vitro to normal epithelial cells.In this study we report the first triple action single-mol. inhibitor SRX3177, which disrupts cancer cell signaling through simultaneously inhibiting CDK4/6, PI3K, and BRD4. SRX3177 displays excellent kinome and BET bromodomain selectivity and marked cytotoxicity across multiple tumor types.Our results demonstrate that SRX3177 is efficacious and non-toxic to normal cells in vitro in a wide range of tumor models suggesting further evaluation of this distinct chemotype in resistant cancer models.