title: Preclinical evaluation of AMG 925, a FLT3/CDK4 dual kinase inhibitor for treating acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) remains a serious unmet medical need. Despite high remission rates with chemotherapy standard-of-care treatment, the disease eventually relapses in a major proportion of patients. Activating Fms-like tyrosine kinase 3 (FLT3) mutations are found in approximately 30% of patients with AML. Targeting FLT3 receptor tyrosine kinase has shown encouraging results in treating FLT3-mutated AML. Responses, however, are not sustained and acquired resistance has been a clinical challenge. Treatment options to overcome resistance are currently the focus of research. We report here the preclinical evaluation of AMG 925, a potent, selective, and bioavailable FLT3/cyclin-dependent kinase 4 (CDK4) dual kinase inhibitor. AMG 925 inhibited AML xenograft tumor growth by 96% to 99% without significant body weight loss. The antitumor activity of AMG 925 correlated with the inhibition of STAT5 and RB phosphorylation, the pharmacodynamic markers for inhibition of FLT3 and CDK4, respectively. In addition, AMG 925 was also found to inhibit FLT3 mutants (e.g., D835Y) that are resistant to the current FLT3 inhibitors (e.g., AC220 and sorafenib). CDK4 is a cyclin D-dependent kinase that plays an essential central role in regulating cell proliferation in response to external growth signals. A critical role of the CDK4-RB pathway in cancer development has been well established. CDK4-specific inhibitors are being developed for treating RB-positive cancer. AMG 925, which combines inhibition of two kinases essential for proliferation and survival of FLT3-mutated AML cells, may improve and prolong clinical responses.
authors: Authors' Affiliation: Amgen Discovery Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California.
authors: Kathleen
authors: K
authors: Keegan
authors: Cong
authors: C
authors: Li
authors: Zhihong
authors: Z
authors: Li
authors: Ji
authors: J
authors: Ma
authors: Mark
authors: M
authors: Ragains
authors: Suzanne
authors: S
authors: Coberly
authors: David
authors: D
authors: Hollenback
authors: John
authors: J
authors: Eksterowicz
authors: Lingming
authors: L
authors: Liang
authors: Margaret
authors: M
authors: Weidner
authors: Justin
authors: J
authors: Huard
authors: Xianghong
authors: X
authors: Wang
authors: Grace
authors: G
authors: Alba
authors: Jessica
authors: J
authors: Orf
authors: Mei-Chu
authors: MC
authors: Lo
authors: Sharon
authors: S
authors: Zhao
authors: Rachel
authors: R
authors: Ngo
authors: Ada
authors: A
authors: Chen
authors: Lily
authors: L
authors: Liu
authors: Timothy
authors: T
authors: Carlson
authors: Christophe
authors: C
authors: Quéva
authors: Lawrence R
authors: LR
authors: McGee
authors: Julio
authors: J
authors: Medina
authors: Alexander
authors: A
authors: Kamb
authors: Dineli
authors: D
authors: Wickramasinghe
authors: Kang
authors: K
authors: Dai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009287:Naphthyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D009374:Neoplasms, Experimental; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: C000589290:2-hydroxy-1-(2-((9-(4-methylcyclohexyl)-9H-pyrido(4',3'-4,5)pyrrolo(2,3-d)pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethanone; D006575:Heterocyclic Compounds, 3-Ring; D009287:Naphthyridines; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D051941:fms-Like Tyrosine Kinase 3; D051358:Cyclin-Dependent Kinase 4; C500026:palbociclib