Uzansertib (INCB053914)

Uzansertib (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 this compound has modest potency (IC50 = 7.1 μM). No kinase other than Per-Arnt-Sim (PAS) kinase is significantly inhibited by INCB053914 (100 nM)[1]. In cell proliferation assays, it 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. This compound synergizes with a variety of cytotoxic and targeted agents, reducing the viability of a panel of hematological tumor cell lines[2].

MOLM-16 (AML), Pfeiffer (DLBCL), KMS-12-PE (MM), and KMS-12-BM (MM) cells (10⁶) are incubated with Uzansertib (INCB053914) at concentrations ranging from 0 (phosphate-buffered saline [PBS]) to 1 μM for 2 hours in RPMI medium. Cells are centrifuged at 1,000 rpm for 10 minutes and lysed with 1× lysis buffer supplemented with 1 mM phenylmethane sulfonyl fluoride and proteinase inhibitor cocktail. Cell lysates are stored at -80°C before determining phosphoprotein and PIM2 levels by Western blotting.

In vivo, single-agent Uzansertib (INCB053914) inhibits Bcl-2-associated death promoter protein phosphorylation and dose-dependently inhibited tumor growth in acute myeloid leukemia and multiple myeloma xenografts[2]. It inhibits tumor growth in a dose-dependent manner in mice bearing MOLM-16 (AML) or KMS-12-BM (MM) tumors. A pharmacokinetic analysis of plasma concentrations of this compound up to 16 hours post oral administration in MOLM-16 and KMS-12-BM tumor-bearing mice suggests dose proportionality[1].