Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3

…, M DeGraffenreid, JT Deignan, J Duquette…

Index: 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, 2014 , vol. 57, # 8 p. 3430 - 3449

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Citation Number: 12

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 ...