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.

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

Uzansertib effectively hampers the growth of multiple myeloma (MM) and other cancer cell lines, including AML, DLBCL, MCL, and T-ALL, demonstrating a significant range in potency with mean GI50 values between 13.2 nM and 230.0 nM[1]. This compound also dose-dependently blocks the phosphorylation of key PIM kinase targets (p70S6K/S6 and 4E-BP1) across various cell lines like MOLM-16 (AML), Pfeiffer (DLBCL), and KMS-12-PE/BM (MM) at concentrations from 0.1 to 1000 nM[1]. Notably, Uzansertib shows heightened efficacy in inhibiting PIM kinase-mediated phosphorylation of BAD in MOLM-16 and KMS-12-BM cells, with mean IC50 values standing at 4 nM and 27 nM, respectively[1].

Administered orally at doses ranging from 25 to 100 mg/kg twice daily for 15 days, Uzansertib effectively suppresses tumor growth in a dose-dependent manner in immunocompromised (severe combined immunodeficiency [SCID]) female mice aged 5-9 weeks with either MOLM-16 (acute myeloid leukemia [AML]) or KMS-12-BM (multiple myeloma [MM]) tumors[1]. Moreover, Uzansertib exhibits dose-dependent inhibition of BAD phosphorylation compared to the control group, achieving half-maximal inhibitory concentrations (IC50) of 70 nM and 145 nM for MOLM-16 and KMS-12-BM tumors, respectively, at 4 hours post-administration[1].