Optimization of Imidazo[4,5-b]pyridine-Based Kinase Inhibitors: Identification of a Dual FLT3/Aurora Kinase Inhibitor as an Orally Bioavailable Preclinical Development Candidate for the Treatment of Acute Myeloid Leukemia

Abstract

Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A Kd = 7.5 nM, Aurora-B Kd = 48 nM), FLT3 kinase (Kd = 6.2 nM), and FLT3 mutants including FLT3-ITD (Kd = 38 nM) and FLT3(D835Y) (Kd = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20–35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4–11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children.

Aurora Isoform Selectivity: Design and Synthesis of Imidazo[4,5-b]pyridine Derivatives as Highly Selective Inhibitors of Aurora-A Kinase in Cells

“…28 In parallel to this work, we also investigated the design and synthesis of Aurora-A-selective inhibitors based on the imidazo[4,5- b ]pyridine scaffold. Herein, we report our medicinal chemistry program aimed at the identification of imidazo[4,5- b ]pyridine- and 7-azaindole-based inhibitors displaying a high degree of selectivity for Aurora-A over Aurora-B.…”

Targeted Drug Discovery for Pediatric Leukemia

“…On the basis of the encouraging pre-clinical results, AT9283 is being tested in relapsed and refractory ALL and AML in a Phase I trial in the UK. A potentially important development is the discovery of compounds that inhibit both FLT3 and aurora kinases; a dual FLT3/aurora kinase inhibitor known simply as compound 27e ( 19 ) may show enhanced clinical efficacy due to synergy between FLT3 and aurora kinase inhibition (Bavetsias et al, 2012). (See Figure 2F for structures of the compounds discussed in this section.…”

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia

“…A plethora of early phase clinical trials are evaluating small molecule inhibitors against these kinases (reviewed in). Preclinical data have shown that inhibition of Aurora A, B and FLT3 kinase by compound 27e led to growth inhibition in an FLT3‐ITD‐positive AML xenograft . AT9283 has shown in vitro activity in cell line models for myeloproliferative disorders with gain of function mutations in JAK2 and in adult phase I/II trials for solid tumors and hematological malignancies .…”