Ariad Pharmaceuticals Inc fka ARIA

[jaybe]

Found this tidbit from Jan. 9 on SciBite from Timmy C., et al. I tried running this through Google translator but apparently it's already in English (kkk). Could LDHA inhibitor be the next molecule? Also first specific mention of fragment-based drug discovery from HB's clan that I can recall.

http://www.ncbi.nlm.nih.gov/pubmed/23302067

J Med Chem. 2013 Jan 9. [Epub ahead of print]
Fragment Growing and Linking Lead to Novel Nanomolar Lactate Dehydrogenase Inhibitors.
Kohlmann A, Zech SG, Li F, Zhou T, Squillace RM, Commodore L, Greenfield MT, Lu X, Miller DP, Huang WS, Qi J, Thomas RM, Wang Y, Zhang S, Dodd R, Liu S, Xu R, Xu Y, Miret JJ, Rivera V, Clackson T, Shakespeare WC, Zhu X, Dalgarno DC.
Source
ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
Abstract
Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway. Cancer cells rely heavily on glycolysis instead of oxidative phosphorylation to generate ATP, a phenomenon known as the Warburg effect. The inhibition of LDH-A by small molecules is therefore of interest for potential cancer treatments. We describe the identification and optimization of LDH-A inhibitors by fragment-based drug discovery. We applied ligand based NMR screening to identify low affinity fragments binding to LDH-A. The dissociation constants (K(d)) and enzyme inhibition (IC(50)) of fragment hits were measured by surface plasmon resonance (SPR) and enzyme assays, respectively. The binding modes of selected fragments were investigated by X-ray crystallography. Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDH-A. Selected molecules inhibited lactate production in cells, suggesting target-specific inhibition in cancer cell lines.