2FVD

Cyclin Dependent Kinase 2 (CDK2) with diaminopyrimidine inhibitor

2FVD の概要

• エントリーDOI: 10.2210/pdb2fvd/pdb
• 分子名称: Cell division protein kinase 2, (4-AMINO-2-{[1-(METHYLSULFONYL)PIPERIDIN-4-YL]AMINO}PYRIMIDIN-5-YL)(2,3-DIFLUORO-6-METHOXYPHENYL)METHANONE (3 entities in total)
• 機能のキーワード: cdk2 ligand, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34417.94

構造登録者

Crowther, R.L.,Lukacs, C.M.,Kammlott, R.U. (登録日: 2006-01-30, 公開日: 2006-10-10, 最終更新日: 2024-02-14)

主引用文献

Chu, X.J.,DePinto, W.,Bartkovitz, D.,So, S.S.,Vu, B.T.,Packman, K.,Lukacs, C.,Ding, Q.,Jiang, N.,Wang, K.,Goelzer, P.,Yin, X.,Smith, M.A.,Higgins, B.X.,Chen, Y.,Xiang, Q.,Moliterni, J.,Kaplan, G.,Graves, B.,Lovey, A.,Fotouhi, N.
Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity.
J.Med.Chem., 49:6549-6560, 2006

PubMed Abstract: The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K(i) > 10 microM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K(i) = 0.001, 0.003, and 0.001 microM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC(50) = 0.08 microM). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

PubMed: 17064073
DOI: 10.1021/jm0606138

実験手法

X-RAY DIFFRACTION (1.85 Å)