Discovery and characterization of 2-anilino-4- (thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents.

The main difficulty in the development of ATP antagonist kinase inhibitors is target specificity, since the ATP-binding motif is present in many proteins. We introduce a strategy that has allowed us to identify compounds from a kinase inhibitor library that block the cyclin-dependent kinases responsible for regulating transcription, i.e.

Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors.

Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds.

Seliciclib, a cell-cycle modulator that acts through the inhibition of cyclin-dependent kinases.

Seliciclib is an inhibitor of cyclin-dependent kinases 2, 7 and 9. Its primary mechanism of action is the inhibition of transcription, resulting in the selective downregulation of rapidly cycling mRNA transcripts, including Mcl-1 and cyclin D1. It possesses antitumour activity as a single agent and also synergises with a wide range of cytotoxic and targeted drugs.

Metabolism of the trisubstituted purine cyclin-dependent kinase inhibitor seliciclib (R-roscovitine) in vitro and in vivo.

Seliciclib (R-roscovitine, CYC202) is a small molecule inhibitor of cyclin-dependent kinases currently in phase II clinical trials as an anticancer agent. We examined the metabolism of seliciclib in vitro and in vivo. Using radiolabeled seliciclib we found that cytochrome P450 (P450)-mediated metabolism in liver microsomes from human, rat, mouse, rabbit, monkey, and dog was rapid to a number of metabolic species, one of the most prevalent being a carboxylate previously identified in urine from rats and mice dosed with seliciclib.

Metabolism and pharmacokinetics of the cyclin-dependent kinase inhibitor R-roscovitine in the mouse.

R-roscovitine (seliciclib, CYC202) is a cyclin-dependent kinase inhibitor currently in phase II clinical trials in patients with cancer. Here, we describe its mouse metabolism and pharmacokinetics as well as the identification of the principal metabolites in hepatic microsomes, plasma, and urine. Following microsomal incubation of R-roscovitine at 10 microg/mL (28 micromol/L) for 60 minutes, 86.

Discovery of a novel family of CDK inhibitors with the program LIDAEUS: structural basis for ligand-induced disordering of the activation loop.

A family of 4-heteroaryl-2-amino-pyrimidine CDK2 inhibitor lead compounds was discovered with the new database-mining program LIDAEUS through in silico screening. Four compounds with IC(50) values ranging from 17 to 0.9 microM were selected for X-ray crystal analysis.

In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine).

CDK2 inhibitors have been proposed as effective anti-cancer therapeutics. We show here that CYC202 (R-roscovitine) is a potent inhibitor of recombinant CDK2/cyclin E kinase activity (IC(50) = 0.10 microM) with an average cytotoxic IC(50) of 15.