Uzansertib

Uzansertib (INCB053914) is an orally active, ATP-competitive pan-PIM kinase inhibitor with IC₅₀s of 0.24 nM, 30 nM, 0.12 nM for PIM1, PIM2, PIM3, respectively. Uzansertib has broad anti-proliferative activity against a variety of hematologic tumor cell lines^[1]. In Vitro: Uzansertib inhibits proliferation in all multiple myeloma (MM) cell lines tested, with mean GI₅₀ 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 IC₅₀, 4 nM and 27 nM, respectively)^[1].
In Vivo: 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, IC₅₀=70 nM; KMS-12-BM tumors, IC₅₀=145 nM) ^[1].