Discovery of a novel phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor against hematologic malignancies and theoretical studies on its PI3Kγ-specific binding mechanisms.

ABSTRACT: Class IB phosphoinositide 3-kinase gamma (PI3Kγ) is vital for regulating intracellular signaling pathways and has become an attractive drug target for the treatment of malignant tumors. In the present study, one potent PI3Kγ inhibitor (JN-PK1) with a novel scaffold against hematologic malignancies was identified based on a series of biological experiments, and then the selective mechanism of PI3Kγ inhibition was explored by a systematic computational method. JN-PK1 shows an effective antiproliferative activity on several cancer cell lines, especially blood cancer cells. Cell-free enzymatic studies demonstrated that JN-PK1 specifically inhibits PI3Kγ at low micromolar concentrations without affecting other isoforms of PI3K. In the cellular context, JN-PK1 potently inhibits PI3K/Akt/mTOR sig

SUBMITTER: Zhu J 

PROVIDER: S-EPMC9087882 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature