8cm8

Publication Abstract from PubMed

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 muM 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 A 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.

Galectin-8N-Selective 4-Halophenylphthalazinone-Galactals Double pi-Stack in a Unique Pocket.,van Klaveren S, Hassan M, Hakansson M, Johnsson RE, Larsson J, Jakopin Z, Anderluh M, Leffler H, Tomasic T, Nilsson UJ ACS Med Chem Lett. 2024 Jul 22;15(8):1319-1324. doi: , 10.1021/acsmedchemlett.4c00212. eCollection 2024 Aug 8. PMID:39140038^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.