Identification and characterization of a novel chemotype MEK inhibitor able to alter the phosphorylation state of MEK1/2.

A small molecule compound, JTP-74057/GSK1120212/trametinib, had been discovered as a very potent antiproliferative agent able to induce the accumulation of CDK inhibitor p15INK4b. To conduct its drug development rationally as an anticancer agent, molecular targets of this compound were identified as MEK1/2 using compound-affinity chromatography. It was shown that JTP-74057 directly bound to MEK1 and MEK2 and allosterically inhibited their kinase activities, and that its inhibitory characteristics were similar to those of the known and different chemotype of MEK inhibitors PD0325901 and U0126.

A novel model of obesity-related diabetes: introgression of the Lepr(fa) allele of the Zucker fatty rat into nonobese Spontaneously Diabetic Torii (SDT) rats.

An fa allele of the leptin receptor gene (Lepr(fa)) of the Zucker fatty rat was introduced into the genome of the Spontaneously Diabetic Torii (SDT) rat, an inbred model of nonobese type 2 diabetes mellitus, through the 'Speed congenic method'. The newly established congenic strain of a SDT rat for Lepr(fa) was maintained by intercrossing between fa-heterozygous littermates, and the phenotypes related to obesity and diabetes were investigated till 32 wks of age. SDT fa/fa rats of both sexes exhibited obesity, adiposity and insulin resistance associated with hyperphagia from the loss of leptin action.