4I9U

Crystal structure of rabbit LDHA in complex with a fragment inhibitor AP26256

Summary for 4I9U

• Entry DOI: 10.2210/pdb4i9u/pdb
• Related: 4I8X 4I9H 4I9N
• Descriptor: L-lactate dehydrogenase A chain, 6-({2-[(5-chloro-2-methoxyphenyl)amino]-2-oxoethyl}sulfanyl)pyridine-3-carboxylic acid (3 entities in total)
• Functional Keywords: cancer, fragment, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Oryctolagus cuniculus (rabbit)
• Cellular location: Cytoplasm: P13491
• Total number of polymer chains: 8
• Total formula weight: 294673.34

Authors

Zhou, T.,Kohlmann, A.,Stephan, Z.G.,Commodore, L.,Greenfield, M.T.,Zhu, X.,Dalgarno, D.C. (deposition date: 2012-12-05, release date: 2013-01-23, Last modification date: 2023-09-20)

Primary citation

Kohlmann, A.,Zech, S.G.,Li, F.,Zhou, T.,Squillace, R.M.,Commodore, L.,Greenfield, M.T.,Lu, X.,Miller, D.P.,Huang, W.S.,Qi, J.,Thomas, R.M.,Wang, Y.,Zhang, S.,Dodd, R.,Liu, S.,Xu, R.,Xu, Y.,Miret, J.J.,Rivera, V.,Clackson, T.,Shakespeare, W.C.,Zhu, X.,Dalgarno, D.C.
Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors.
J.Med.Chem., 56:1023-1040, 2013

PubMed 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.

PubMed: 23302067
DOI: 10.1021/jm3014844

Experimental method

X-RAY DIFFRACTION (2.5 Å)