Uzansertib (INCB053914) is a potent ATP-competitive pan-PIM kinase inhibitor. It exhibits exceptional inhibitory activity against PIM1, PIM2, and PIM3 with IC50 values of 0.24 nM, 30 nM, and 0.12 nM, respectively. Furthermore, Uzansertib demonstrates significant anti-proliferative effects against an assorted range of hematologic tumor cell lines.

Pim3:0.12 nM (IC50), Pim2:30 nM (IC50), Pim1:0.24 nM (IC50)

Uzansertib inhibits proliferation in all multiple myeloma (MM) cell lines tested, with mean GI 50 values ranging from 13.2 nM to 230.0 nM in AML, MM, DLBCL, MCL, and T-ALL cell lines[1]. Uzansertib (0.1, 0.3, 1, 3, 10, 30, 100, 300, 1000 nM) inhibits the phosphorylation of downstream PIM kinase substrates (p70S6K/S6 and 4E-BP1) in a dose-dependent manner in MOLM-16 (AML), Pfeiffer (DLBCL), and KMS-12-PE/BM (MM) cell lines[1]. PIM kinase-mediated phosphorylation of BAD in MOLM-16 and KMS-12-BM cells is particularly sensitive to inhibition by Uzansertib (mean IC 50 , 4 nM and 27 nM, respectively)[1].

Uzansertib (25-100 mg/kg; PO; twice a day; for 15 days) inhibits tumor growth in a dose-dependent manner in mice bearing MOLM-16 (AML) or KMS-12-BM (MM)[1]. Uzansertib demonstrates a dose-dependent inhibition of BAD phosphorylation relative to vehicle at 4 hours post dose (MOLM-16 tumors, IC 50 =70 nM; KMS-12-BM tumors, IC 50 =145 nM)[1]. Animal Model: Female immune compromised (severe combined immunodeficiency [SCID]) mice (5-9 weeks of age) bearing MOLM-16 (AML) or KMS-12-BM (MM)[1]Dosage: 25, 50, 75, 100 mg/kg Administration: PO; twice a day; for 15 days Result: Inhibited tumor growth in a dose-dependent manner in mice.