BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe.

The branched-chain amino acid transaminases (BCATs) are enzymes that catalyze the first reaction of catabolism of the essential branched-chain amino acids to branched-chain keto acids to form glutamate. They are known to play a key role in different cancer types. Here, we report a new structural class of BCAT1/2 inhibitors, (trifluoromethyl)pyrimidinediones, identified by a high-throughput screening campaign and subsequent optimization guided by a series of X-ray crystal structures. Our potent dual BCAT1/2 inhibitor BAY-069 displays high cellular activity and very good selectivity. Along with a negative control (BAY-771), BAY-069 was donated as a chemical probe to the Structural Genomics Consortium.

High throughput screening in agrochemical research.

The demand for new herbicides, insecticides and fungicides led to a steady increase in the number of compounds being tested to find novel market products. To keep pace with the rising workload, high throughput screening (HTS) technologies have been introduced. In agrochemical research miniaturised in vivo tests on whole real target organisms are now possible and are an integral part of the screening cascade. A complementary target based in vitro HTS has also been established in agrochemical research. Target based HTS allows a directed approach towards untouched market shares by novel modes of action. Selection of the best suited targets is the most crucial issue in this approach. Genomic methods thereby deliver many essential genes as candidate targets. Consideration of further criteria such as druggability notably narrows down the number of promising targets. Though target to hit to lead progression still is as in pharmaceutical research a complex and therefore risky process, the implementation of novel bioscience technologies has entailed the transition to an integrated innovative agrochemical research perspective.

Flufenacet herbicide treatment phenocopies the fiddlehead mutant in Arabidopsis thaliana.

In order to study the mode of action of herbicides we conducted a pilot study analysing phenotype and gene expression of flufenacet- and benfuresate-treated Arabidopsis thaliana (L) Heynhoe plants. Treatments with either herbicide caused phenocopies of the known Arabidopsis mutant fiddlehead, displaying fused organs and the typical fiddlehead-like inflorescence. Herbicide treatments of other plant species, including monocots, also gave rise to analogous organ fusions, indicating the presence of the target in a broad range of plants. Furthermore, many other herbicides with a proposed similar mode of action, eg chloroacetanilides, produced comparable fusion phenotypes in plants. The fiddlehead gene encodes a putative very-long-chain fatty acid elongase (VLCFAE), which corroborates earlier biochemical results pointing to the inhibition of VLCFA synthesis as mode of action of flufenacet. Gene expression profiles of herbicide-treated plants using the first 8247 gene Arabidopsis gene array of Affymetrix provided additional clues in support of inhibition of VLCFA synthesis. We discuss fiddlehead-like elongases as plant specific targets for flufenacet and many other herbicides.