4lyn

Crystal structure of cyclin-dependent kinase 2 (cdk2-wt) complex with (2s)-n-(5-(((5-tert-butyl-1,3-oxazol-2-yl)methyl)sulfanyl)-1,3-thiazol-2-yl)-2-phenylpropanamide

spinqualitylabelsall models 4lyn, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4lyn is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1YG Gene: CDK2, CDKN2 (Homo sapiens) Activity: Cyclin-dependent kinase, with EC number 2.7.11.22 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed High throughput screening identified 2-acetamido-thiazolylthio acetic ester 1 as an inhibitor of cyclin-dependent kinase 2 (CDK2). Because this compound is inactive in cells and unstable in plasma, we have stabilized it to metabolic hydrolysis by replacing the ester moiety with a 5-ethyl-substituted oxazole as in compound 14. Combinatorial and parallel synthesis provided a rapid analysis of the structure-activity relationship (SAR) for these inhibitors of CDK2, and over 100 analogues with IC(50) values in the 1-10 nM range were rapidly prepared. The X-ray crystallographic data of the inhibitors bound to the active site of CDK2 protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues displayed potent and broad spectrum antiproliferative activity across a panel of tumor cell lines in vitro. In addition, A2780 ovarian carcinoma cells undergo rapid apoptosis following exposure to CDK2 inhibitors of this class. Mechanism of action studies have confirmed that the phosphorylation of CDK2 substrates such as RB, histone H1, and DNA polymerase alpha (p70 subunit) is reduced in the presence of compound 14. Further optimization led to compounds such as water soluble 45, which possesses a favorable pharmacokinetic profile in mice and demonstrates significant antitumor activity in vivo in several murine and human models, including an engineered murine mammary tumor that overexpresses cyclin E, the coactivator of CDK2. Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2: synthesis, X-ray crystallographic analysis, and biological activities.,Kim KS, Kimball SD, Misra RN, Rawlins DB, Hunt JT, Xiao HY, Lu S, Qian L, Han WC, Shan W, Mitt T, Cai ZW, Poss MA, Zhu H, Sack JS, Tokarski JS, Chang CY, Pavletich N, Kamath A, Humphreys WG, Marathe P, Bursuker I, Kellar KA, Roongta U, Batorsky R, Mulheron JG, Bol D, Fairchild CR, Lee FY, Webster KR J Med Chem. 2002 Aug 29;45(18):3905-27. PMID:12190313 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cell division protein kinase 2

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