N-(Cycloalkylamino)acyl-2-aminothiazole Inhibitors of Cyclin-Dependent Kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a Highly Efficacious and Selective Antitumor Agent

Abstract

N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.

Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors

“…Recently, crystal structures of CDK2 in complex with different aminothiazoles were also published [30][31][32][33]. In these crystal structures, the thiazole ring-binding mode is the same as that of our compounds.…”

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

“…5), (R)-roscovitine (CYC202/Seliciclib; refs. 11, 12), R547 (13,14), SNS-032 (15), PD-0332991 (16,17), AZD5438 (18,19), ZK 304709 (20,21), AG-024322, AT7519, and P276-00 (21).…”

Discovery and Evaluation of Dual CDK1 and CDK2 Inhibitors

“…However, many of these small-molecule CDK inhibitors either lack potency, selectivity, or suitable physical properties. For example, a small-molecule CDK inhibitor (BMS-387032) currently in clinical trials has IC 50 s of 480, 48, and 925 nmol/L against recombinant cyclin B1/CDK1, cyclin E/CDK2, and cyclin D/CDK4 kinase complexes, respectively (30). In addition, the maximum tolerated dose (MTD) of BMS-387032 is 48 mg/kg, and efficacy is observed in an A2780 tumor xenograft model at 36 to 48 dosed once a day for 8 days, showing a narrow therapeutic index (31).…”