Dual Targeting of Aurora Kinases with AMG 900 Exhibits Potent Preclinical Activity Against Acute Myeloid Leukemia with Distinct Post-Mitotic Outcomes.

Abstract

Aurora kinase A and B have essential and non-overlapping roles in mitosis, with elevated expression in a subset of human cancers, including acute myeloid leukemia (AML). In this study, pan-aurora kinase inhibitor (AKI) AMG 900 distinguishes itself as an anti-leukemic agent that is more uniformly potent against a panel of AML cell lines than are isoform-selective AKIs and classic AML drugs. AMG 900 inhibited AML cell growth by inducing polyploidization and/or apoptosis. AMG 900 and aurora-B-selective inhibitor AZD1152-hQPA showed comparable cellular effects on AML lines that do not harbor a FLT3-ITD mutation. AMG 900 was active against P-glycoprotein-expressing AML cells resistant to AZD1152-hQPA and was effective at inducing expression of megakaryocyte-lineage markers (CD41, CD42) on human CHRF-288-11 cells and mouse Jak2 V617F cells. In MOLM-13 cells, inhibition of p-histone H3 by AMG 900 was associated with polyploidy, extra centrosomes, accumulation of p53 protein, apoptosis, and cleavage of Bcl-2 protein. Co-administration of cytarabine (Ara-C) with AMG 900 potentiated cell killing in a subset of AML lines, with evidence of attenuated polyploidization. AMG 900 inhibited the proliferation of primary human bone marrow cells in culture, with a better proliferation recovery profile relative to classic antimitotic drug docetaxel. In vivo, AMG 900 significantly reduced tumor burden in a systemic MOLM-13 xenograft model where we demonstrate the utility of 3'-deoxy-3'-18F-fluorothymidine [18F]FLT positron emission tomographic (PET)-CT imaging to measure the antiproliferative effects of AMG 900 in skeletal tissues in mice.

• Authors: Marc Payton, Hung-Kam Cheung, Maria Stefania S Ninniri, Christian Marinaccio, William C Wayne, Kelly Hanestad, John D Crispino, Gloria Juan, Angela Coxon
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 12 Pg. 2575-2585 (12 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 30266802 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• 2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate
• N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine
• Organophosphates
• Phthalazines
• Protein Isoforms
• Proto-Oncogene Proteins c-bcl-2
• Quinazolines
• Tumor Suppressor Protein p53
• Aurora Kinases

Topics

• Animals
• Apoptosis (drug effects)
• Aurora Kinases (antagonists & inhibitors, metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• G1 Phase (drug effects)
• Humans
• Leukemia, Myeloid, Acute (pathology)
• Megakaryocytes (drug effects, metabolism, pathology)
• Mice
• Mitosis (drug effects)
• Organophosphates (pharmacology)
• Phthalazines (pharmacology)
• Polyploidy
• Protein Isoforms (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Quinazolines (pharmacology)
• Tumor Burden
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays