9BK3
Crystal structure of Lactate dehydrogenase in complex with 4-((4-(1-methyl-1H-imidazole-2-carbonyl)phenyl)amino)-4-oxo-2-(4-(trifluoromethyl)phenyl)butanoic acid (R-enantiomer, orthorhombic P form)
This is a non-PDB format compatible entry.
Summary for 9BK3
| Entry DOI | 10.2210/pdb9bk3/pdb |
| Descriptor | L-lactate dehydrogenase A chain, CHLORIDE ION, MALONATE ION, ... (5 entities in total) |
| Functional Keywords | lactate dehydrogenase, oxidoreductase, ldha, inhibitor complex, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 157370.06 |
| Authors | Lovell, S.,Cooper, A.,Battaile, K.P.,Sharma, H. (deposition date: 2024-04-26, release date: 2024-07-10) |
| Primary citation | Sharma, H.,Mondal, S.,Urquiza, U.,Esparza, C.,Bartlett, S.,Santa-Pinter, L.,Hill, H.,White, M.,Sharma, P.,Luckett-Chastain, L.,Cooper, A.,Rasel, M.,Gao, P.,Battaile, K.P.,Shukla, S.K.,Lovell, S.,Ihnat, M.A. Synthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer. Eur.J.Med.Chem., 275:116598-116598, 2024 Cited by PubMed Abstract: Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma (PDAC). Despite some progress, current LDH inhibitors have poor structural and physicochemical properties or exhibit unfavorable pharmacokinetics that have hampered their development. The present study reports the synthesis and biological evaluation of a novel class of LDHA inhibitors comprising a succinic acid monoamide motif. Compounds 6 and 21 are structurally related analogs that demonstrated potent inhibition of LDHA with ICs of 46 nM and 72 nM, respectively. We solved cocrystal structures of compound 21-bound to LDHA that showed that the compound binds to a distinct allosteric site between the two subunits of the LDHA tetramer. Inhibition of LDHA correlated with reduced lactate production and reduction of glycolysis in MIA PaCa-2 pancreatic cancer cells. The lead compounds inhibit the proliferation of human pancreatic cancer cell lines and patient-derived 3D organoids and exhibit a synergistic cytotoxic effect with the OXPHOS inhibitor phenformin. Unlike current LDHA inhibitors, 6 and 21 have appropriate pharmacokinetics and ligand efficiency metrics, exhibit up to 73% oral bioavailability, and a cumulative half-life greater than 4 h in mice. PubMed: 38925013DOI: 10.1016/j.ejmech.2024.116598 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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