Selective and novel cyclin-dependent kinases 4 inhibitor: synthesis and biological evaluation
A series of novel LEE011 derivatives containing pyridine N-oxide were designed, synthesized and evaluated. Systematic study of the structure-activity relationship (SAR) improves the selectivity for CDK4 and led to the identification of compound 9a. The compound showed comparable CDK4 kinase activity with ribociclib and greater selectivity over the closely related CDK6 kinase. The selective CDK4 inhibitor 9a has been demonstrated the antitumor activity via G1 phase cell cycle arrest, as well as dual CDK4/CDK6 inhibitor ribociclib and significantly down-regulated the activity of CDK4-cyclinD-Rb pathway of tumor cells. Taken together, this compound may act as promising lead compound for further development of new CDK4 inhibitors.
This work was supported by the Project of Science and Technology Assistance in Developing Countries (KY201501006) and the National Natural Science Foundation of China (81470354) and the Natural Science Foundation of Tianjin (17JCQNJC13500) and National key scientific research project (2013CB967201).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Delano WL (2014) The PyMOL molecular graphics system, version 1.7; Schrödinger LLC, New YorkGoogle Scholar
- Gonda M, Nieves M, Nunes E, Lopez de Cerain A, Monge A, Lavaggi ML, Gonzalez M, Cerecetto H (2013) Phenazine N,N[prime or minute]-dioxide scaffold as selective hypoxic cytotoxin pharmacophore. Structural modifications looking for further DNA topoisomerase II-inhibition activity. MedChemComm 4:595–607CrossRefGoogle Scholar