PD 166285 dihydrochloride

PD0166285 dihydrochloride, a substrate of P-gp, is a WEE1 inhibitor and a weak Myt1 inhibitor with IC50 values of 24 and 72 nM, respectively. PD0166285 dihydrochloride exhibits an IC50 of 3.433 μM for Chk1[1].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> Wee1

IC50: 24 nM (WEE1), 72 nM (Myt1), 3.433 μM (Chk1)[1].

PD0166285 (0.5 μM) dramatically inhibits irradiation-induced Cdc2 phosphorylation at the Tyr-15 and Thr-14 in seven of seven cancer cell lines[1]. PD0166285 sensitizes radiation-induced cell killing in p53 mutant HT29 cells and in the E6-transfected, p53-null ovarian cancer cell line PA-1 but to a lesser extent in p53 wild-type PA-1 cells. PD0166285 abrogates irradiation-induced G2 arrest and significantly increases mitotic cell populations[1]. PD0166285 acts as a radiosensitizer to sensitize cells to radiation-induced cell death with a sensitivity enhancement ratio of 1.23[1]. Western Blot Analysis[1] Cell Line: Human and mouse cancer cell lines (HCT116, HT29, DLD-1, HCT8, H460, HeLa, C 26). Concentration: 0.5 μM. Incubation Time: 4 h. Result: Inhibited Cdc2Y15 and CdcT14 phosphorylation.

Animal Model: Wild-type, Abcg2-/-, Abcb1a/b-/- and Abcb1a/b;Abcg2-/- FVB mice[2]. Dosage: 5 mg/kg. Administration: IV. Result: Cmax is about 400 ng/mL. P-gp, but not BCRP, limited the brain penetration of PD0166285.

[1]. Wang Y, et al. Radiosensitization of p53 mutant cells by PD0166285, a novel G(2) checkpoint abrogator. Cancer Res. 2001 Nov 15;61(22):8211-7.

[2]. Mark C de Gooijer, et al. ATP-binding cassette transporters limit the brain penetration of Wee1 inhibitors. Invest New Drugs. 2018 Jun;36(3):380-387.