5D1J

CRYSTAL STRUCTURE OF CYCLIN-DEPENDENT KINASE 2 (CDK2-WT) COMPLEX WITH N-[5-[[[5-(1,1-DIMETHYLETHYL)-2-OXAZOLYL] METHYL]THIO]-2-THIAZOLYL]-4-PIPERIDINECARBOXAMIDE (BMS-387032)

Summary for 5D1J

• Entry DOI: 10.2210/pdb5d1j/pdb
• Descriptor: Cyclin-dependent kinase 2, N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide (3 entities in total)
• Functional Keywords: kinase, mitosis, cell cycle, transferase-transferase inhibit complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941
• Total number of polymer chains: 1
• Total formula weight: 34357.02

Authors

Sack, J.S. (deposition date: 2015-08-04, release date: 2015-08-12, Last modification date: 2024-03-06)

Primary citation

Misra, R.N.,Xiao, H.Y.,Kim, K.S.,Lu, S.,Han, W.C.,Barbosa, S.A.,Hunt, J.T.,Rawlins, D.B.,Shan, W.,Ahmed, S.Z.,Qian, L.,Chen, B.C.,Zhao, R.,Bednarz, M.S.,Kellar, K.A.,Mulheron, J.G.,Batorsky, R.,Roongta, U.,Kamath, A.,Marathe, P.,Ranadive, S.A.,Sack, J.S.,Tokarski, J.S.,Pavletich, N.P.,Lee, F.Y.F.,Webster, K.R.,Kimball, S.D.
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
J.Med.Chem., 47:1719-, 2004

PubMed 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.

PubMed: 15027863
DOI: 10.1021/jm0305568

Experimental method

X-RAY DIFFRACTION (1.8 Å)