9FXZ

Galectin-8 N-terminal carbohydrate recognition domain in complex with 4-(bromophenyl)phthalazinone D-galactal ligand

Replaces:  8CM8

Summary for 9FXZ

• Entry DOI: 10.2210/pdb9fxz/pdb
• Descriptor: Galectin-8, 4-(4-bromophenyl)-2-[[(2~{R},3~{R},4~{R})-2-(hydroxymethyl)-3-oxidanyl-3,4-dihydro-2~{H}-pyran-4-yl]oxymethyl]phthalazin-1-one, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: galectin, phthalazinone, inhibitor, sugar binding protein, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 72662.14

Authors

Van Klaveren, S.,Hakansson, M.,Diehl, C.,Nilsson, N.J. (deposition date: 2024-07-02, release date: 2025-07-16)

Primary citation

van Klaveren, S.,Hassan, M.,Hakansson, M.,Johnsson, R.E.,Larsson, J.,Jakopin, Z.,Anderluh, M.,Leffler, H.,Tomasic, T.,Nilsson, U.J.
Galectin-8N-Selective 4-Halophenylphthalazinone-Galactals Double pi-Stack in a Unique Pocket.
Acs Med.Chem.Lett., 15:1319-1324, 2024

PubMed Abstract: 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-(-bromophenyl)phthalazinone derivative displaying a 34 μM 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 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.

PubMed: 39140038
DOI: 10.1021/acsmedchemlett.4c00212

Experimental method

X-RAY DIFFRACTION (1.3 Å)