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

Summary for 4LYN

• Entry DOI: 10.2210/pdb4lyn/pdb
• Descriptor: Cyclin-dependent kinase 2, (2S)-N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)-2-phenylpropanamide (3 entities in total)
• Functional Keywords: kinase, mitosis, cell cycle, 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: 34378.03

Authors

Sack, J.S. (deposition date: 2013-07-31, release date: 2013-10-02, Last modification date: 2024-04-03)

Primary citation

Kim, K.S.,Kimball, S.D.,Misra, R.N.,Rawlins, D.B.,Hunt, J.T.,Xiao, H.-Y.,Lu, S.,Qian, L.,Han, W.C.,Shan, W.,Mitt, T.,Cai, Z.-W.,Poss, M.A.,Zhu, H.,Sack, J.S.,Tokarski, J.S.,Chang, C.Y.,Pavletich, N.,Kamath, A.,Humphreys, W.G.,Marathe, P.,Bursuker, I.,Kellar, K.A.,Roongta, U.,Batorsky, R.,Mulheron, J.G.,Bol, D.,Fairchild, C.R.,Lee, F.Y.,Webster, K.R.
Discovery of Aminothiazole Inhibitors of Cyclin-Dependent Kinase 2: Synthesis, X-Ray Crystallographic Analysis, and Biological Activities
J.Med.Chem., 45:3905-3927, 2002

PubMed Abstract: 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.

PubMed: 12190313
DOI: 10.1021/jm0201520

Experimental method

X-RAY DIFFRACTION (2 Å)