4TTH

Crystal structure of a CDK6/Vcyclin complex with inhibitor bound

Replaces:  4P41

Summary for 4TTH

• Entry DOI: 10.2210/pdb4tth/pdb
• Descriptor: 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)
• Functional Keywords: kinase, transferase-cell cycle-inhibitor complex, transferase/cell cycle/inhibitor
• Biological source: Saimiriine herpesvirus 2 (SaHV-2); More
• Cellular location: Cytoplasm: Q00534
• Total number of polymer chains: 2
• Total formula weight: 66067.25

Authors

Piper, D.E.,Walker, N.,Wang, Z. (deposition date: 2014-06-20, release date: 2014-08-06, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.9 Å)