Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor

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 intravenous route. With the objective
to address the oral bioavailability issue of this scaffold, four series
of rohitukine derivatives were prepared and screened for Cdk inhibition
and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative
IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC50 1.9 nM) kinase 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 inhibited the cell
growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved
71% oral bioavailability with in vivo efficacy in pancreatic, colon,
and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump
liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically
stable. The preclinical data presented herein indicates the potential
of 11d for advancement in clinical studies.