Zotiraciclib

Zotiraciclib (TG02; SB1317) is an orally active JAK2/FLT3/CDK2 inhibitor with IC₅₀ values of 13 nM, 73 nM and 56 nM, respectively. Zotiraciclib inhibits cancer cell proliferation, tumor growth and the activity of CYP2D6. Zotiraciclib exhibits high plasma protein binding rate, Caco-2 permeability and tissue distribution capacity, as well as metabolic stability in human and canine liver microsomes. Zotiraciclib achieves tumor growth inhibition in nude mouse models of colon cancer and lymphoma xenografts. Zotiraciclib can be used for research related to colon cancer, B-cell lymphoma, advanced leukemia, acute leukemia and multiple myeloma^[1][2]. In Vitro:Zotiraciclib (up to 10 μM; 48 h) potently inhibits proliferation of HL-60, HCT-116, Ramos, COLO205, and DU145 cancer cell lines with IC₅₀ values ranging from 0.033 μM to 0.14 μM^[1].
Zotiraciclib (8-1000 nM; 24 h) inhibits phospho-Rb in HCT-116 cells, with detectable effects at 40 nM and complete inhibition at 200 nM after 24 h of treatment^[1].
Zotiraciclib (0.05-25 μM; 5-60 min depending on isoform) inhibits human CYP2D6 with an IC₅₀ of 0.95 μM, but does not inhibit CYP1A2, 2C9, 2C19, or 3A4 at concentrations up to 25 μM^[1].
Zotiraciclib (5 μM; 120 min) exhibits high permeability with low efflux across Caco-2 cell monolayers, with Papp values of 28.0 × 10^-6 cm/s (apical-to-basolateral) and 27.4 × 10^-6 cm/s (basolateral-to-apical) at 5 μM for 120 min^[2]. In Vivo:Zotiraciclib (50-75 mg/kg; p.o.; 3 times per week; 15 days) administered orally at 75 mg/kg 3 times per week achieves a mean tumor growth inhibition of 82% in HCT-116 colon cancer xenografts in nude mice^[1].
Zotiraciclib (15-75 mg/kg; p.o., i.p.; once daily, 2 days on/5 days off, 5 days on/5 days off; 14 days) administered orally at 75 mg/kg on a 2 days on/5 days off schedule achieves 42% TGI, and intraperitoneally at 15 mg/kg on a 5 days on/5 days off schedule achieves 63% TGI in Ramos B-cell lymphoma xenografts in nude mice^[1].