9BK2

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 (S-enantiomer, monoclinic P form)

これはPDB形式変換不可エントリーです。

9BK2 の概要

• エントリーDOI: 10.2210/pdb9bk2/pdb
• 分子名称: L-lactate dehydrogenase A chain, DIMETHYL SULFOXIDE, (2S)-4-[4-(1-methyl-1H-imidazole-2-carbonyl)anilino]-4-oxo-2-[4-(trifluoromethyl)phenyl]butanoic acid, ... (5 entities in total)
• 機能のキーワード: lactate dehydrogenase, oxidoreductase, ldha, inhibitor complex, structural genomics, seattle structural genomics center for infectious disease, ssgcid, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 158255.10

構造登録者

Lovell, S.,Cooper, A.,Battaile, K.P.,Sharma, H. (登録日: 2024-04-26, 公開日: 2024-07-10, 最終更新日: 2024-09-04)

主引用文献

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

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: 38925013
DOI: 10.1016/j.ejmech.2024.116598

実験手法

X-RAY DIFFRACTION (1.85 Å)