(E/Z)-Zotiraciclib ((E/Z)-TG02) effectively inhibits CDK2, JAK2, and FLT3 with IC50s of 13 nM, 73 nM, and 56 nM, respectively.

CDK2:13 nM, FLT3:56 nM, JAK2:73 nM

(E/Z)-Zotiraciclib has a highly novel kinase inhibitory spectrum inhibiting 17 kinases from a panel of 63, 11 of which are CDK/JAK/FLT family members. Human CYP1A2, 3A4, 2C9, and 2C19 isoforms are not inhibited by (E/Z)-Zotiraciclib at the highest tested concentration of 25 μM, but (E/Z)-Zotiraciclib inhibits CYP2D6 with an IC50 of 0.95 μM, approximately at the plasma Cmax?observed at the maximum tolerated dose. (E/Z)-Zotiraciclib inhibits cell proliferation concentrations in HCT-116 with an IC50 of 0.079 μM and HL-60 with an IC50 of 0.059 μM[1]. (E/Z)-Zotiraciclib is a novel small molecule potent CDK/JAK2/FLT3 inhibitor and mainly metabolized by CYP3A4 and CY1A2 in vitro[2].

Treatment with (E/Z)-Zotiraciclib (75 mg/kg p.o. q.d. 3×/week) significantly inhibits the growth of tumors with a mean TGI of 82%, while the lower dose(50 mg/kg p.o. 3×/week) is marginally effective. Treatment with (E/Z)-Zotiraciclib using either regime significantly inhibits the growth of tumors with mean TGIs of 42% and 63% for the oral and ip delivery methods, respectively[1]. In pharmacokinetic studies, (E/Z)-Zotiraciclib shows moderate to high systemic clearance (relative to liver blood flow), high volume of distribution (>0.6 L/kg), the oral bioavailability of 24%, ~4 and 37% in mice, rats, and dogs, respectively; and extensive tissue distribution in mice[2].