PD-184352

A potent, ATP non-competitive MEK1/2 inhibitor with IC50 of 17 nM in cell-based assays, displays 100-fold more selective for MEK1/2 than MEK5; reduces pMAPK levels in multiple tumor cells, prevents cell cycle progression and induces G1 block; suppresses growth of colon tumors in vivo.Colon Cancer Phase 2 Discontinued (In Vitro) :CI-1040 directly inhibits MEK1 with an IC50 of 17 nM. It has also been shown to have little activity against a panel of related kinases with IC50 values more than 2.5 orders of magnitude higher. Treatment of whole cells with CI-1040 completely inhibits the mitogen-stimulated phosphorylation of ERK. CI-1040 at a concentration of 1 μM is found to inhibit phosphorylation of ERK1 and ERK2 by 99% and 92%, respectively in MDA-MB-231 breast cancer cells. CI-1040 induces apoptosis and inhibits proliferation in U-937 cells in a dose and time-dependent manner. CI-1040 induces a significant increase in PUMA mRNA and protein levels. (In Vivo) :The systemic administration of the MEK inhibitor CI-1040 reduces adenoma formation to a third and significantly restores lung structure. The proliferation rate of lung cells of mice treated with CL-1040 is decreased without any obvious effects on differentiation of pneumocytes.