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
  • 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.