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)

spinqualitylabelsall models 9bk3, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9bk3 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: A1AR0, CL, MLI Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease LDHA_HUMAN Defects in LDHA are the cause of glycogen storage disease type 11 (GSD11) [MIM:612933. A metabolic disorder that results in exertional myoglobinuria, pain, cramps and easy fatigue. Function LDHA_HUMAN Publication Abstract from PubMed 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 IC(50)s 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. Synthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer.,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 KP, Shukla SK, Lovell S, Ihnat MA Eur J Med Chem. 2024 Sep 5;275:116598. doi: 10.1016/j.ejmech.2024.116598. Epub , 2024 Jun 17. PMID:38925013 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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