SPH3643: A novel cyclin-dependent kinase 4/6 inhibitor with good anticancer efficacy and strong blood-brain barrier permeability.

Abstract

The cyclin-dependent kinase (CDK)4/6-cyclin D1-Rb-p16/ink4a pathway is responsible for regulating cell progression past the G1 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 RbSer780 and arrested the MCF-7 cancer cells at G0 /G1 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.

• Authors: XueMei Liao, Yuan Hong, Yu Mao, Na Chen, Qian Wang, Zhe Wang, LeDuo Zhang, Li Wang, Chen Shi, WeiJun Shi, Hui Ge, AnDi Li, Xin Li, GuangXin Xia, YanJun Liu
• Journal: Cancer science (Cancer Sci) Vol. 111 Issue 5 Pg. 1761-1773 (May 2020) ISSN: 1349-7006 [Electronic] England
• PMID: 32103527 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Retinoblastoma Protein
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Blood-Brain Barrier (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors, metabolism)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors, metabolism)
• Female
• Humans
• MCF-7 Cells
• Mice
• Mice, Nude
• Neoplasms (drug therapy, metabolism, pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Retinoblastoma Protein (metabolism)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays