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 Jak2V617F 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 anti-mitotic 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)–computed tomographic (CT) imaging to measure the anti-proliferative effects of AMG 900 in skeletal tissues in mice.

Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer

“…Reports have shown that AMG900 inhibited the growth of glioblastoma cells in vitro ultimately leading to cell cycle arrest and senescence [ 135 ]. In MOLM-13 AML cell line, treatment with AMG900 was linked to inhibition of histone H3 phosphorylation, polyploidy and increased apoptosis with the upregulation of p53 [ 136 ]. The IC50 concentrations of AMG900 on breast cancer cell lines are shown in Table S1 [ 137 ].…”

Phthalazine‐based VEGFR‐2 inhibitors: Rationale, design, synthesis, in silico, ADMET profile, docking, and anticancer evaluations

“…Among these, sorafenib (I), the 1,4-disubstituted phthalazine derivatives, vatalanib (II), AAC789 (III), AMG 900 (IV), and IM-023911 (V) revealed potent inhibitory activity against VEGFR-2 in nanomolar levels of IC 50 . [12,13] Sorafenib is an FDA-approved antiangiogenic drug that shares the above pharmacophoric features. [14] The phthalazine ring is a vital pharmacophoric scaffold present in the core structures of many anticancer molecules [11,[15][16][17][18][19] with potent activity against hepatocellular carcinoma, [18] colon cancer, [11] and breast cancer, [19] and as degraders of VEGFR-2.…”

The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?

“…Several Aurora kinase inhibitors have progressed through preclinical testing and into phase I or phase II trials, including Aurora A (MLN8237, MK-5108, ENMD-2076 [130], the latter also targeting other kinases), Aurora B (AZD-1152 and AZD-2811), and a number of dual or pan-Aurora inhibitors (AS703569/MSC1992371A [131], MK-0457, AT9283, GSK1070916 [132], AMG 900 [133], PHA-739358). However, few drugs reached advanced clinical phase development in acute leukemias, due to low activity and/or intolerability of a significant patient proportion to the required dose.…”