Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads with Varying Binding Modes Identified by Fragment Screening

Inhibitors
of mitochondrial branched chain aminotransferase (BCATm),
identified using fragment screening, are described. This was carried
out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that
bound to BCATm, which were subsequently progressed to X-ray crystallography,
where a number of exemplars showed significant diversity in their
binding modes. The hits identified were supplemented by searching
and screening of additional analogues, which enabled the gathering
of further X-ray data where the original hits had not produced liganded
structures. The fragment hits were optimized using structure-based
design, with some transfer of information between series, which enabled
the identification of ligand efficient lead molecules with micromolar
levels of inhibition, cellular activity, and good solubility.