INCB053914 INCB053914 is a novel, ATP-competitive, small molecule, pan-inhibitor of PIM kinases with IC50 values of 0.24 nM, 30 nM and 0.12 nM for PIM1, PIM2 and PIM3 respectively in biochemical assays.
In vitro
INCB053914 potently inhibits the activities of all three PIM isozymes with half maximal inhibitory concentration (IC50) values in the order of PIM1 ≈ PIM3 < PIM2. It is highly selective against a panel of more than 50 kinases (>475-fold selectivity), except for RSK2 for which INCB053914 has modest potency (IC50 = 7.1 μM). No kinase other than Per-Arnt-Sim (PAS) kinase is significantly inhibited by INCB053914 (100 nM). In cell proliferation assays, INCB053914 is active as a single agent in the majority of cell lines derived from different hematological malignancies, including MM, AML, DLBCL, MCL and T-ALL, with IC50 values ranging from 3-300 nM. INCB053914 synergizes with a variety of cytotoxic and targeted agents, reducing the viability of a panel of hematological tumor cell lines.
In vivo
single-agent INCB053914 inhibits Bcl-2-associated death promoter protein phosphorylation and dose-dependently inhibited tumor growth in acute myeloid leukemia and multiple myeloma xenografts. INCB053914 inhibits tumor growth in a dose-dependent manner in mice bearing MOLM-16 (AML) or KMS-12-BM (MM) tumors. A pharmacokinetic analysis of INCB053914 plasma concentrations up to 16 hours post oral administration in MOLM-16 and KMS-12-BM tumor-bearing mice suggests dose proportionality.
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