1. Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
- Author
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Li Z, Wang X, Eksterowicz J, Gribble MW Jr, Alba GQ, Ayres M, Carlson TJ, Chen A, Chen X, Cho R, Connors RV, DeGraffenreid M, Deignan JT, Duquette J, Fan P, Fisher B, Fu J, Huard JN, Kaizerman J, Keegan KS, Li C, Li K, Li Y, Liang L, Liu W, Lively SE, Lo MC, Ma J, McMinn DL, Mihalic JT, Modi K, Ngo R, Pattabiraman K, Piper DE, Queva C, Ragains ML, Suchomel J, Thibault S, Walker N, Wang X, Wang Z, Wanska M, Wehn PM, Weidner MF, Zhang AJ, Zhao X, Kamb A, Wickramasinghe D, Dai K, McGee LR, and Medina JC
- Subjects
- Animals, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Dogs, Drug Discovery, Heterocyclic Compounds, 3-Ring pharmacology, Humans, Macaca fascicularis, Naphthyridines pharmacology, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors pharmacology, Rats, Structure-Activity Relationship, U937 Cells, fms-Like Tyrosine Kinase 3 genetics, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Heterocyclic Compounds, 3-Ring chemical synthesis, Naphthyridines chemical synthesis, Protein Kinase Inhibitors chemical synthesis, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
- 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.
- Published
- 2014
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