3R8U

CDK2 in complex with inhibitor RC-1-132

3R8U の概要

• エントリーDOI: 10.2210/pdb3r8u/pdb
• 関連するPDBエントリー: 3QL8 3QQF 3QQG 3QQH 3QQJ 3QQK 3QQL 3QRT 3QRU 3QTQ 3QTR 3QTS 3QTU 3QTW 3QTX 3QTZ 3QU0 3QWJ 3QWK 3QX2 3QX4 3QXO 3QXP 3QZF 3QZG 3QZH 3QZI 3R1Q 3R1S 3R1Y 3R28 3R6X 3R71 3R73 3R7E 3R7I 3R7U 3R7V 3R7Y 3R83 3R8L 3R8M 3R8P 3R8V 3R8Z 3R9D 3R9H 3R9N 3R9O 3RAH 3RAI 3RAK 3RAL 3RJC 3RK5 3RK7 3RK9 3RKB 3RM6 3RM7 3RMF 3RNI 3ROY 3RPO 3RPR 3RPV 3RPY 3RZB 3S00 3S0O 3S1H 3SQQ
• 分子名称: Cyclin-dependent kinase 2, [4-amino-2-(prop-2-en-1-ylamino)-1,3-thiazol-5-yl](naphthalen-2-yl)methanone (3 entities in total)
• 機能のキーワード: protein kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, centrosome: P24941
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35070.73

構造登録者

Betzi, S.,Alam, R.,Han, H.,Becker, A.,Schonbrunn, E. (登録日: 2011-03-24, 公開日: 2012-10-31, 最終更新日: 2023-09-13)

主引用文献

Schonbrunn, E.,Betzi, S.,Alam, R.,Martin, M.P.,Becker, A.,Han, H.,Francis, R.,Chakrasali, R.,Jakkaraj, S.,Kazi, A.,Sebti, S.M.,Cubitt, C.L.,Gebhard, A.W.,Hazlehurst, L.A.,Tash, J.S.,Georg, G.I.
Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases.
J.Med.Chem., 56:3768-3782, 2013

PubMed Abstract: Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009-0.0015 μM) from a single hit compound with weak inhibitory activity (IC50 = 15 μM), discovered by high-throughput screening. Structure-based design was performed using 35 cocrystal structures of CDK2 liganded with distinct analogues of the parent compound. The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4, and CDK6. Compound 51 inhibited the proliferation of 13 out of 15 cancer cell lines with IC50 values between 0.27 and 6.9 μM, which correlated with the complete suppression of retinoblastoma phosphorylation and the onset of apoptosis. Combined, the results demonstrate the potential of this new inhibitors series for further development into CDK-specific chemical probes or therapeutics.

PubMed: 23600925
DOI: 10.1021/jm301234k

実験手法

X-RAY DIFFRACTION (2 Å)