| PD0325901 is selective and non ATP-competitive mitogenic extracellular kinase 1/2 (MEK1/2) inhibitor with an IC50 of 0.33 nM. 1 μM PD0325901 induces a time-dependent reduction in pERK 1/2 (Thr202/Thr204), with maximum and significant reduction of pERK1/2 at 4 hours after treating SKMEL-28 human melanoma cells with PD0325901, and partial recovery of the protein at 24 and 48 hours after treatment. PD0325901 (1 μM) reduces cyclin D1 protein expression at 24 and 48 hours after treatment and decreases thymidine kinase 1 (TK1) protein levels in a time-dependent manner in SKMEL-28 cells.[1] PD0325901 potently (IC50, 20-50 nM) inhibits the growth of human melanoma cell lines with (M14, A375P, M, and SM, ME10538, ME4686, JR8) or without (ME4405 and ME13923) BRAF mutations. ME1007 and ME8959, both of which have wild-type BRAF, are slightly more resistant to PD0325901-mediated growth inhibition (IC50, ??00 nM). Besides, PD0325901 strikingly reduces M14 clonogenic growth, with an IC50 of approximately 0.1 nM.[2] The IG50 of PD0325901 is 11 nM for a papillary thyroid carcinomas (PTC) cell line TPC-1 and 6.3 nM for another papillary thyroid carcinomas (PTC) cell lin K2. PD0325901 at concentrations of 100, 10, or 1 nM suppresses the cell growth by 80%, 75%, and 27% in K2 cells, and by 58%, 40%, and 26% in TPC-1 cells, respectively.[3] In SKMEL-28 tumor xenografts, tumor volume changes from 168.0 mm3 (pretreatment group) to 135.8 and 43.2 mm3 at days 1 and 10, respectively, following treatment with treatment with PD0325901 (25 mg/kg). In contrast, tumor volume changes from 168.0 mm3 to 181.2 mm3 and 248.0 mm3 at days 1 and 10, respectively, following treatment with vehicle. In HCT116 tumor xenografts, tumor volume changes from 106.7 mm3 (pretreatment group) to 82.9 and 128.5 mm3 at days 1 and 10, respectively, following treatment with treatment with PD0325901 (25 mg/kg). In contrast, tumor volume changes from 168.0 mm3 to 136.7 mm3 and 542.3 mm3 at days 1 and 10, respectively, following treatment with vehicle.[1] Furthermore, daily treatment with PD0325901 at doses of 5 and 25 mg/kg completely suppresses the growth of SKMEL28 and Colo205 BRAF (V600E) mutant xenografts. PD0325901 treatment of SKMEL103 (NRAS (Q61R)), SKMEL30 (NRAS (Q61R)) and SKMEL31 (RAS/BRAF-WT) xenografts at a dose of 5 mg/kg only delays tumour growth, with complete growth suppression requiring 25 mg/kg.[4] |
