E-viri
Recenzirano
-
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
Journal of medicinal chemistry, 04/2014, Letnik: 57, Številka: 8Journal Article
We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido4′,3′:4,5pyrrolo2,3-dpyrimidine 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.
