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

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

  • ACS Med Chem Lett. 2024 Jul 22;15(8):1319-1324. doi: 10.1021/acsmedchemlett.4c00212.
Sjors van Klaveren 1 2,  Mujtaba Hassan 1,  Maria Håkansson 3,  Richard E Johnsson 4,  Jessica Larsson 4,  Žiga Jakopin 2,  Marko Anderluh 2,  Hakon Leffler 5,  Tihomir Tomašič 2,  Ulf J Nilsson 1
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Lund University, Naturvetarvägen 14, 223 62, Lund, Sweden.
  • 2 Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
  • 3 SARomics Biostructures AB, Medicon Village, SE-223 81, Lund, Sweden.
  • 4 Red Glead Discovery AB, Medicon Village, SE-223 81, Lund, Sweden.
  • 5 Department of Laboratory Medicine, Section MIG, Lund University, BMC-C1228b, Klinikgatan 28, 221 84, Lund, Sweden.
PMID: 39140038 DOI: 10.1021/acsmedchemlett.4c00212
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-(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.

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