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: Kathleen Keegan, Cong Li, Zhihong Li, Ji Ma, Mark Ragains, Suzanne Coberly, David Hollenback, John Eksterowicz, Lingming Liang, Margaret Weidner, Justin Huard, Xianghong Wang, Grace Alba, Jessica Orf, Mei-Chu Lo, Sharon Zhao, Rachel Ngo, Ada Chen, Lily Liu, Timothy Carlson, Christophe Quéva, Lawrence R McGee, Julio Medina, Alexander Kamb, Dineli Wickramasinghe, Kang Dai
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 4 Pg. 880-9 (Apr 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24526162 (Publication Type: Journal Article)

Chemical References

• 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
• Heterocyclic Compounds, 3-Ring
• Naphthyridines
• Phenylurea Compounds
• Piperazines
• Protein Kinase Inhibitors
• Pyridines
• Niacinamide
• Sorafenib
• fms-Like Tyrosine Kinase 3
• Cyclin-Dependent Kinase 4
• palbociclib

Topics

• Animals
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors)
• Dose-Response Relationship, Drug
• Heterocyclic Compounds, 3-Ring (administration & dosage, pharmacokinetics, therapeutic use)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, pathology)
• Mice
• Mice, Nude
• Naphthyridines (administration & dosage, pharmacokinetics, therapeutic use)
• Neoplasms, Experimental
• Niacinamide (analogs & derivatives, pharmacology)
• Phenylurea Compounds (pharmacology)
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (administration & dosage, pharmacokinetics)
• Pyridines (pharmacology)
• Signal Transduction (drug effects)
• Sorafenib
• U937 Cells
• Xenograft Model Antitumor Assays
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors)