2. Academic Validation
  3. Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3

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

  • J Med Chem. 2014 Apr 24;57(8):3430-49. doi: 10.1021/jm500118j.
Zhihong Li 1,  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
Affiliations

Affiliation

  • 1 Departments of †Therapeutic Discovery, ‡Oncology Research, §Pharmaceutics, and ∥Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
PMID: 24641103 DOI: 10.1021/jm500118j
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.

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