1 research outputs found
Discovery of 8‑Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3‑<i>d</i>]pyrimidine-6-carbonitrile (<b>7x</b>) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)
The
success of imatinib, a BCR-ABL inhibitor for the treatment
of chronic myelogenous leukemia, has created a great impetus for the
development of additional kinase inhibitors as therapeutic agents.
However, the complexity of cancer has led to recent interest in polypharmacological
approaches for developing multikinase inhibitors with low toxicity
profiles. With this goal in mind, we analyzed more than 150 novel
cyano pyridopyrimidine compounds and identified structure–activity
relationship trends that can be exploited in the design of potent
kinase inhibitors. One compound, 8<b>-</b>cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyridoÂ[2,3-<i>d</i>]Âpyrimidine-6-carbonitrile (<b>7x</b>), was found
to be the most active, inducing apoptosis of tumor cells at a concentration
of approximately 30–100 nM. In vitro kinase profiling revealed
that <b>7x</b> is a multikinase inhibitor with potent inhibitory
activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report
the synthesis, structure–activity relationship, kinase inhibitory
profile, in vitro cytotoxicity, and in vivo tumor regression studies
by this lead compound