Conformational Adaption May Explain the Slow Dissociation Kinetics of Roniciclib (BAY 1000394), a Type I CDK Inhibitor with Kinetic Selectivity for CDK2 and CDK9

• DOI: 10.1021/acschembio.6b00074
• Publication Date: 2016-04-19T11:20:28Z
• Authors: Pelin Ayaz; Dorothee Andres; Dennis A. Kwiatko...; Carl-Christian Kolbe; Philip Lienau; Gerhard Siemeister; Ulrich Lücking; Christian M. Steg...
• Keywords: CDK inhibitor

Roniciclib (BAY 1000394) is a type I pan-CDK (cyclin-dependent kinase) inhibitor which has revealed potent efficacy in xenograft cancer models. Here, we show that roniciclib displays prolonged residence times on CDK2 and CDK9, whereas other CDKs are transient, thus giving rise to kinetic selectivity of roniciclib. Surprisingly, variation the substituent at 5-position pyrimidine scaffold results changes up 3 orders magnitude drug–target time. X-ray cocrystal structures have DFG-loop adaption for 5-(trifluoromethyl) substituent, while hydrogen bromo substituents DFG loop remains its characteristic position. In tumor cells, CDK9 reflected sustained inhibitory effect retinoblastoma protein (RB) phosphorylation, indicating target time may contribute engagement antitumor efficacy.