Narazaciclib

Narazaciclib (ON123300), a strong and brain-penetrant^[1] multi-kinase inhibitor, inhibits CDK4 (IC₅₀=3.9 nM), Ark5 (IC₅₀=5 nM), PDGFRβ (IC₅₀=26 nM), FGFR1 (IC₅₀=26 nM), RET (IC₅₀=9.2 nM), and FYN (IC₅₀=11 nM). Single agent Narazaciclib causes a dose-dependent suppression of phosphorylation of Akt as well as activation of Erk in brain tumors^[2]. Narazaciclib inhibits CDK6 with an IC₅₀ of 9.82 nM^[3]. In Vitro:Narazaciclib (ON123300) inhibits U87 glioma cell proliferation with an IC₅₀ of 3.4±0.1 μM^[2]. Narazaciclib (1 and 10 μM) inhibits cell proliferation in a panel of 11 glioma models including a patient-derived model (GBM10)^[2].
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^[2]. ON123300 inhibits PI3Kδ with the IC₅₀ of 144nM^[3]. 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 (T_1/2) is 1.5 h for 5 mg/kg and 25 mg/kg in plasma^[2].