SPH3643: A novel CDK4/6 inhibitor with good anti-cancer efficacy and strong blood-brain barrier permeability.

The cyclin-dependent kinase (CDK)4/6-cyclin D1-Rb-p16/ink4a pathway is responsible for regulating cell progression past the G(1) restriction point during the cell cycle. The development of a majority of human tumors is associated with dysregulation of this pathway, resulting in increased cancer cell proliferation. Both CDK4 and CDK6, well-validated cancer drug targets, function primarily as catalytic enzymes that mediate the phosphorylation of retinoblastoma protein (Rb). Here, we determined that SPH3643 is a novel potent antiproliferative agent that inhibits CDK4/6 kinase activity. In biochemical assays, SPH3643 showed more potent inhibition of both CDK4 and CDK6 than did 2 published CDK4/6 inhibitors, LY2835219 and palbociclib, and had better selectivity than LY2835219. Further in vitro study revealed that SPH3643 blocked Cdk/Rb signaling by inhibiting the phosphorylation of Rb-Ser780 and arrested the MCF-7 cancer cells at G(0)/G(1) phase, resulting in marked inhibition of the proliferation of Rb-positive cancer cell lines. In vivo SPH3643 treatment in mice bearing xenograft tumor models of breast cancer, colon cancer, acute myelocytic leukemia, and glioblastoma resulted in significant decreases in tumor growth. SPH3643 was able to particularly strongly inhibit glioblastoma (U87-MG) cell growth in the brains of orthotopic carcinoma xenograft mice due to its high degree of intracerebral penetration and significant persistence in this setting. Together these results revealed that SPH3643 is a potent, orally active small-molecule inhibitor of CDK4/6 with robust anticancer efficacy and a high degree of blood-brain barrier permeability.