Phosphatases from Bacteria Isolated from the Arabian Sea and Cochin Estuary

This study aims to reveal the ability of bacteria isolated from Cochin estuary and the Arabian Sea to produce phosphatases, important characters of the enzymes, its ability to utilize organophosphorus compounds as source of phosphate and also their role in degradation of organophosphorus pesticides. It deals with isolation, identification and screening of bacteria for phosphatase production, and it describes the effect of cultural conditions on growth and phosphatase production. The effect of various factors like pH, NaCl concentration, temperature of incubation, carbon source, period of incubation etc. on growth and phosphatase production by the two selected species were studied to establish suitable environment for phosphatase production by these bacteria. In this study regulation of phosphatase synthesis, characteristics of acid and alkaline phosphatases are discussed

Discovery of MAP855, an efficacious and selective MEK1/2 inhibitor with ATP-competitive mode of action

Mutations in MEK1/2 have been described as a resistance mechanism to BRAF/MEK inhibitor treatment. We report the discovery of a novel ATP-competitive MEK inhibitor with efficacy in wildtype (WT) and mutant MEK models. Starting from a HTS hit, we obtained selective, cellularly active compounds that showed equipotent inhibition of WT MEK and a panel of MEK mutant cell lines. Using a structure-based approach, the optimisation addressed the liabilities by systematic analysis of molecular matched pairs (MMP) and ligand conformation. Addition of only 3 heavy atoms to early tool com-pound 6 removed Cyp3A4 liabilities and increased cellular potency by 100-fold, while reducing logP by 5 units. Profiling of MAP855, compound 30 in PK-PD and efficacy studies in BRAF-mutant models showed comparable efficacy to clinical MEK inhibitors. Compound 30 is a novel highly potent and selective MEK1 kinase inhibitor with equipotent inhibition of WT and mutant MEK whose drug like properties allow further investigation in the mutant MEK setting upon BRAF/MEK therapy