8OMJ

hKHK-C in complex with compound 28

Summary for 8OMJ

• Entry DOI: 10.2210/pdb8omj/pdb
• Descriptor: Ketohexokinase, [3-[[6-[(3~{a}~{R},6~{a}~{S})-2,3,3~{a},4,6,6~{a}-hexahydro-1~{H}-pyrrolo[3,4-c]pyrrol-5-yl]-3-cyano-4-(trifluoromethyl)pyridin-2-yl]amino]-4-methylsulfanyl-phenyl]methoxy-methyl-phosphinic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: khk, ketohexokinase, sugar binding kinase, inhibitor complex, sugar binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 69400.30

Authors

Pautsch, A.,Ebenhoch, R. (deposition date: 2023-03-31, release date: 2024-07-10, Last modification date: 2024-09-04)

Primary citation

Heine, N.,Weber, A.,Pautsch, A.,Gottschling, D.,Uphues, I.,Bauer, M.,Ebenhoch, R.,Magarkar, A.,Nosse, B.,Kley, J.T.
Discovery of BI-9787, a potent zwitterionic ketohexokinase inhibitor with oral bioavailability.
Bioorg.Med.Chem.Lett., 112:129930-129930, 2024

PubMed Abstract: Fructose metabolism by ketohexokinase (KHK) is implicated in a variety of metabolic disorders. KHK inhibition is a potential therapeutic strategy for the treatment of diseases including diabetes, non-alcoholic fatty liver disease, and non-alcoholic steatohepatitis. The first small-molecule KHK-inhibitors have entered clinical trials, but it remains unclear if systemic inhibition of KHK by small-molecules will eventually benefit patients. Here we report the discovery of BI-9787, a potent, zwitterionic KHK inhibitor characterized by high permeability and favorable oral rat pharmacokinetics. BI-9787 was identified by optimizing chemical starting points generated via a ligand-based virtual screening of Boehringer's virtual library of synthetically accessible compounds (BICLAIM). It serves as a high-quality in vitro and in vivo tool compound for investigating the role of fructose metabolism in disease.

PubMed: 39179180
DOI: 10.1016/j.bmcl.2024.129930

Experimental method

X-RAY DIFFRACTION (1.978 Å)