Abstract

Discovery and Preclinical Development of IIIM-290, an Orally Active CDK Inhibitor

Ram Vishwakarma, Director, Indian Institute of Integrative Medicine

Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via IV route. With the objective to address oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cytotoxicity. The 2,6-dichloro-styryl analogue IIIM-290 (11d) showed potent inhibition of Cdk-9/T1 (IC50 1.9 nM) and Molt-4/MIAPaCa-2 cell growth (GI50 < 1.0 µM) and was found to be highly selective for cancer cells over normal fibroblast-cells. It inhibits the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It possess 71% oral bioavailability and display in-vivo efficacy in pancreatic, colon and leukemia xenografts at 50 mpk, po. It does not have CYP/ efflux-pump liability, is not mutagenic/genotoxic or cardiotoxic and is metabolically-stable. The discovery and preclinical data will be presented indicating potential of IIIM-290 (11d) for advancement in clinical studies.