PDBsum entry 4tth

Transferase/cell cycle/inhibitor

PDB id: 4tth

Contents

Protein chains

244 a.a.

256 a.a.

Ligands

24V

Waters ×10

PDB id:

4tth

Name:

Transferase/cell cycle/inhibitor

Title:

Crystal structure of a cdk6/vcyclin complex with inhibitor bound

Structure:

Cyclin homolog. Chain: a. Synonym: v-cyclin. Engineered: yes. Cyclin-dependent kinase 6. Chain: b. Synonym: cell division protein kinase 6,serine/threonine-protein kinase plstire. Engineered: yes

Source:

Saimiriine herpesvirus 2. Sahv-2. Organism_taxid: 10383. Strain: 11. Gene: 72, eclf2. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Homo sapiens. Human.

Resolution:

2.90Å R-factor: 0.240 R-free: 0.337

Authors:

D.E.Piper,N.Walker,Z.Wang

Key ref:

Z.Li et al. (2014). 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. PubMed id: 24641103 DOI: 10.1021/jm500118j

Date:

20-Jun-14 Release date: 06-Aug-14

Supersedes:

4p41

Protein chain

Q01043  (CGH2_SHV21) -  Cyclin homolog from Saimiriine herpesvirus 2 (strain 11)

Seq: 254 a.a.

Struc: 244 a.a.

Protein chain

Q00534  (CDK6_HUMAN) -  Cyclin-dependent kinase 6 from Homo sapiens

Seq: 326 a.a.

Struc: 256 a.a.

Enzyme reactions

• Enzyme class 1: Chain A: E.C.?
• Enzyme class 2: Chain B: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/jm500118j

J Med Chem 57:3430-3449 (2014)

PubMed id: 24641103

Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.

Z.Li, X.Wang, J.Eksterowicz, M.W.Gribble, G.Q.Alba, M.Ayres, T.J.Carlson, A.Chen, X.Chen, R.Cho, R.V.Connors, M.DeGraffenreid, J.T.Deignan, J.Duquette, P.Fan, B.Fisher, J.Fu, J.N.Huard, J.Kaizerman, K.S.Keegan, C.Li, K.Li, Y.Li, L.Liang, W.Liu, S.E.Lively, M.C.Lo, J.Ma, D.L.McMinn, J.T.Mihalic, K.Modi, R.Ngo, K.Pattabiraman, D.E.Piper, C.Queva, M.L.Ragains, J.Suchomel, S.Thibault, N.Walker, X.Wang, Z.Wang, M.Wanska, P.M.Wehn, M.F.Weidner, A.J.Zhang, X.Zhao, A.Kamb, D.Wickramasinghe, K.Dai, L.R.McGee, J.C.Medina.

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.