8SZ3

Structure of human beta 1,3-N-acetylglucosaminyltransferase 2 with compound 7j

Summary for 8SZ3

• Entry DOI: 10.2210/pdb8sz3/pdb
• Descriptor: N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, N-[(1S)-1-(5-bromopyridin-2-yl)ethyl]-3-[(2R)-3,3-dimethylbutan-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazole-5-carboxamide, ... (5 entities in total)
• Functional Keywords: acetylglucosaminyltransferase, inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 94884.24

Authors

Sudom, A.,Min, X. (deposition date: 2023-05-26, release date: 2023-12-06, Last modification date: 2024-10-23)

Primary citation

Jackson, J.J.,Siegmund, A.C.,Bai, W.J.,Reed, A.B.,Birkholz, A.B.,Campuzano, I.D.G.,Crequer-Grandhomme, A.,Hu, R.,Modak, R.V.,Sudom, A.,Javier, N.,Sanders, C.,Lo, M.C.,Xie, F.,Cee, V.J.,Manzanillo, P.,Allen, J.G.
Imidazolone as an Amide Bioisostere in the Development of beta-1,3- N -Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors.
J.Med.Chem., 66:16120-16140, 2023

PubMed Abstract: B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation. In the development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres. This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochemical and pharmacokinetic properties. Herein, we present the synthesis, SAR, X-ray cocrystal structures, and PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.

PubMed: 37988652
DOI: 10.1021/acs.jmedchem.3c01517

Experimental method

X-RAY DIFFRACTION (2.32 Å)