| Literature DB >> 24641103 |
Zhihong Li1, Xianghong Wang, John Eksterowicz, Michael W Gribble, Grace Q Alba, Merrill Ayres, Timothy J Carlson, Ada Chen, Xiaoqi Chen, Robert Cho, Richard V Connors, Michael DeGraffenreid, Jeffrey T Deignan, Jason Duquette, Pingchen Fan, Benjamin Fisher, Jiasheng Fu, Justin N Huard, Jacob Kaizerman, Kathleen S Keegan, Cong Li, Kexue Li, Yunxiao Li, Lingming Liang, Wen Liu, Sarah E Lively, Mei-Chu Lo, Ji Ma, Dustin L McMinn, Jeffrey T Mihalic, Kriti Modi, Rachel Ngo, Kanaka Pattabiraman, Derek E Piper, Christophe Queva, Mark L Ragains, Julia Suchomel, Steve Thibault, Nigel Walker, Xiaodong Wang, Zhulun 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.
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.Entities:
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Year: 2014 PMID： 24641103 DOI： 10.1021/jm500118j
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446