Galectin-8N-Selective 4-Halophenylphthalazinone-Galactals Double π-Stack in a Unique Pocket.

Autor: van Klaveren S; Department of Chemistry, Faculty of Science, Lund University, Naturvetarvägen 14, 223 62, Lund, Sweden.; Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia., Hassan M; Department of Chemistry, Faculty of Science, Lund University, Naturvetarvägen 14, 223 62, Lund, Sweden., Håkansson M; SARomics Biostructures AB, Medicon Village, SE-223 81, Lund, Sweden., Johnsson RE; Red Glead Discovery AB, Medicon Village, SE-223 81, Lund, Sweden., Larsson J; Red Glead Discovery AB, Medicon Village, SE-223 81, Lund, Sweden., Jakopin Ž; Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia., Anderluh M; Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia., Leffler H; Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden., Tomašič T; Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia., Nilsson UJ; Department of Chemistry, Faculty of Science, Lund University, Naturvetarvägen 14, 223 62, Lund, Sweden.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 Jul 22; Vol. 15 (8), pp. 1319-1324. Date of Electronic Publication: 2024 Jul 22 (Print Publication: 2024).
DOI: 10.1021/acsmedchemlett.4c00212
Abstrakt: Galectin-8 contains two different carbohydrate recognition domains (CRDs). Selective inhibitors for at least one CRD are desirable for galectin-8 biology studies and potentially for pharmacological purposes. Structure-guided design led to the discovery of potent and selective glycomimetic-heterocycle hybrid ligands, with a 4-( p -bromophenyl)phthalazinone derivative displaying a 34 μM K d for galectin-8N (N-terminal CRD), no binding to galectin-8C (C-terminal CRD), -1, -3, -4N, -7, -9C, or -9N, and >40-fold selectivity over galectin-4C. Selectivity was achieved with the halogenated 4-phenylphthalazinone moiety occupying a galectin-8N-specific sub-pocket. A 1.30 Å resolution X-ray structure revealed the phthalazinone moiety stacking with Arg45 and the 4-bromophenyl moiety stacking both Arg59 and Tyr141 of galectin-8N. Physicochemical and in vitro ADME studies revealed a desirable LogD, which also translated to good passive permeability. The chemical, microsome, and plasma stability support these compounds as promising tool compounds and candidates for hit-to-lead optimization.
Competing Interests: The authors declare the following competing financial interest(s): UJN and HL are shareholders in Galecto Biotech Inc.
(© 2024 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE
Externí odkaz: