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

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• 作者：Zhihong Li ; Xianghong Wang ; John Eksterowicz ; Michael W. Gribble ; Jr. ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3430-3449
• 全文大小：904K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

We describe the structural optimization of a lead compound <b>1b> that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4鈥?3鈥?4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of <b>28b> (<b>AMG 925b>), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound <b>28b> 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,聽D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound <b>28b> leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.