Zotiraciclib

Zotiraciclib (TG02; SB1317) is a potent inhibitor of CDK2, JAK2, and FLT3 for the treatment of cancer, with IC50s of 13, 73, and 56 nM for CDK2, JAK2 and FLT3, respectively.

Zotiraciclib (SB1317) has a highly novel kinase inhibitory spectrum inhibiting 17 kinases from a panel of 63, 11 of which are CDK/JAK/FLT family members. The others, Lck, Fyn, Fms, TYRO3, ERK5, and p38δ, are implicated in inflammatory and proliferative processes. Human CYP1A2, 3A4, 2C9, and 2C19 isoforms are not inhibited by Zotiraciclib at the highest tested concentration of 25 μM, but Zotiraciclib inhibits CYP2D6 with IC50=0.95 μM, approximately at the plasma Cmax observed at the maximum tolerated dose. Zotiraciclib inhibits cell proliferation concentrations in HCT-116 (IC50=0.079 μM) and HL-60 (IC50=0.059 μM)[1]. Zotiraciclib (SB1317) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. Zotiraciclib is mainly metabolized by CYP3A4 and CY1A2 in vitro. Zotiraciclib does not inhibit any of the major human CYPs in vitro except CYP2D6 (IC50=1 μM). Zotiraciclib does not significantly induce CYP1A and CYP3A4 in human hepatocytes in vitro[2].

Treatment with Zotiraciclib (SB1317) at 75 mg/kg po q.d. 3×/week significantly inhibits the growth of tumors with a mean TGI of 82%, while the lower dose of 50 mg/kg po 3×/week is marginally effective. Treatment with 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 Zotiraciclib shows moderate to high systemic clearance (relative to liver blood flow), high volume of distribution (>0.6 L/kg), oral bioavailability of 24%, ~4 and 37% in mice, rats and dogs, respectively; and extensive tissue distribution in mice[2].

[1]. William AD, et al. Discovery of kinase spectrum selective macrocycle (16E)-14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene (SB1317/TG02), a potent inhibitor of cyclin dependent kina
[2]. Pasha MK, et al. Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor. Drug Metab Lett. 2012 Mar;6(1):33-42.