Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3

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 an...

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Veröffentlicht in:	Journal of medicinal chemistry 2014-04, Vol.57 (8), p.3430-3449
Hauptverfasser:	Li, Zhihong, Wang, Xianghong, Eksterowicz, John, Gribble, Michael W, Alba, Grace Q, Ayres, Merrill, Carlson, Timothy J, Chen, Ada, Chen, Xiaoqi, Cho, Robert, Connors, Richard V, DeGraffenreid, Michael, Deignan, Jeffrey T, Duquette, Jason, Fan, Pingchen, Fisher, Benjamin, Fu, Jiasheng, Huard, Justin N, Kaizerman, Jacob, Keegan, Kathleen S, Li, Cong, Li, Kexue, Li, Yunxiao, Liang, Lingming, Liu, Wen, Lively, Sarah E, Lo, Mei-Chu, Ma, Ji, McMinn, Dustin L, Mihalic, Jeffrey T, Modi, Kriti, Ngo, Rachel, Pattabiraman, Kanaka, Piper, Derek E, Queva, Christophe, Ragains, Mark L, Suchomel, Julia, Thibault, Steve, Walker, Nigel, Wang, Xiaodong, Wang, Zhulun, Wanska, Malgorzata, Wehn, Paul M, Weidner, Margaret F, Zhang, Alex J, Zhao, Xiaoning, Kamb, Alexander, Wickramasinghe, Dineli, Dai, Kang, McGee, Lawrence R, Medina, Julio C
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Cyclin-Dependent Kinase 4 - antagonists & inhibitors Cyclin-Dependent Kinase 6 - antagonists & inhibitors Cytochrome P-450 CYP3A Cytochrome P-450 CYP3A Inhibitors Dogs Drug Discovery fms-Like Tyrosine Kinase 3 - antagonists & inhibitors fms-Like Tyrosine Kinase 3 - genetics Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - pharmacology Humans Macaca fascicularis Naphthyridines - chemical synthesis Naphthyridines - pharmacology Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Rats Structure-Activity Relationship U937 Cells
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Zusammenfassung:	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 (FLT3WT) and induced cell death in MOLM13 (FLT3ITD) and even in MOLM13 (FLT3ITD, 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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm500118j