ON123300

ON123300 is a potent, multi-targeted kinase inhibitor with IC50 of 5, 3.9, 26, 26, 9.2 and 11 nM for ARK5, CDK4, PDGFRβ, FGFR1, RET and FYN, respectively; inhibits U87 glioma cell proliferation with IC50 3.4 uM, and reduces phosphorylation of Akt, yet it also unexpectedly induces Erk activation and prevents phosphorylation of C-Raf S259; suppresses phosphorylation of Akt as well as activation of Erk in brain tumors in vivo; also exhibits potent activity against mantle cell lymphomas both in vitro and in vivo, triggers apoptosis and inhibition of the Rb and PI3K/AKT pathways. (In Vitro) :Narazaciclib (ON123300) inhibits U87 glioma cell proliferation with an IC50 of 3.4±0.1 μM. Narazaciclib (1 and 10 μM) inhibits cell proliferation in a panel of 11 glioma models including a patient-derived model (GBM10) .Narazaciclib (6.3 μM; 1 h) reduces phosphorylation of Akt and its downstream signaling components, P70S6K, 40S rpS6 and Rb S780, yet ON123300 induces Erk activation in U87 cells; both in a dose- and time-dependent manner. ON123300 inhibits PI3Kδ with the IC50 of 144nM. (In Vivo) :Narazaciclib (ON123300) decreases p-Akt expression and increases p-Erk activity in brain tumors upon administration at both IV doses of 5 mg/kg and 25 mg/kg in U87 brain tumor-bearing mouse. The half-life (T1/2) is 1.5 h for 5 mg/kg and 25 mg/kg in plasma.