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Get Free AccessWe 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.
Zhihong Li, Xianghong Wang, John Eksterowicz, Michael W. Gribble, Grace Q. Alba, Merrill Ayres, Timothy J. Carlson, Ada Chen, Xiaoqi Chen, Robert Cho, Richard Connors, Michael DeGraffenreid, Jeffrey Deignan, Jason Duquette, Pingchen Fan, Benjamin Fisher, Jiasheng Fu, Justin Huard, Jacob A. Kaizerman, Kathleen S. Keegan, Cong Li, Kexue Li, Yunxiao Li, Lingming Liang, Wen Liu, Sarah Lively, Mei-Chu Lo, Ji Ma, Dustin L. McMinn, Jeffrey T. Mihalic, Kriti Modi, Rachel Ngo, Kanaka Pattabiraman, Derek E. Piper, Christophe Quéva, Mark L. Ragains, Julia Suchomel, Steve Thibault, Nigel P.C. Walker, Xiaodong Wang, Zhong Lin Wang, Malgorzata Wanska, Paul M. Wehn, Margaret F. Weidner, Alex J. Zhang, Xiaoning Zhao, Alexander Kamb, Dineli Wickramasinghe, Kang Dai, Lawrence R. McGee, Julio C. Medina (2014). Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3. , 57(8), DOI: https://doi.org/10.1021/jm500118j.
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Type
Article
Year
2014
Authors
51
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1021/jm500118j
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