4TTH

Crystal structure of a CDK6/Vcyclin complex with inhibitor bound

「4P41」から置き換えられました

4TTH の概要

• エントリーDOI: 10.2210/pdb4tth/pdb
• 分子名称: Cyclin homolog, Cyclin-dependent kinase 6, 9-cyclopentyl-N-(5-piperazin-1-ylpyridin-2-yl)pyrido[4,5]pyrrolo[1,2-d]pyrimidin-2-amine, ... (4 entities in total)
• 機能のキーワード: kinase, transferase-cell cycle-inhibitor complex, transferase/cell cycle/inhibitor
• 由来する生物種: Saimiriine herpesvirus 2 (SaHV-2); 詳細
• 細胞内の位置: Cytoplasm: Q00534
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66067.25

構造登録者

Piper, D.E.,Walker, N.,Wang, Z. (登録日: 2014-06-20, 公開日: 2014-08-06, 最終更新日: 2023-09-27)

主引用文献

Li, Z.,Wang, X.,Eksterowicz, J.,Gribble, M.W.,Alba, G.Q.,Ayres, M.,Carlson, T.J.,Chen, A.,Chen, X.,Cho, R.,Connors, R.V.,DeGraffenreid, M.,Deignan, J.T.,Duquette, J.,Fan, P.,Fisher, B.,Fu, J.,Huard, J.N.,Kaizerman, J.,Keegan, K.S.,Li, C.,Li, K.,Li, Y.,Liang, L.,Liu, W.,Lively, S.E.,Lo, M.C.,Ma, J.,McMinn, D.L.,Mihalic, J.T.,Modi, K.,Ngo, R.,Pattabiraman, K.,Piper, D.E.,Queva, C.,Ragains, M.L.,Suchomel, J.,Thibault, S.,Walker, N.,Wang, X.,Wang, Z.,Wanska, M.,Wehn, P.M.,Weidner, M.F.,Zhang, A.J.,Zhao, X.,Kamb, A.,Wickramasinghe, D.,Dai, K.,McGee, L.R.,Medina, J.C.
Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
J.Med.Chem., 57:3430-3449, 2014

PubMed Abstract: We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

PubMed: 24641103
DOI: 10.1021/jm500118j

実験手法

X-RAY DIFFRACTION (2.9 Å)