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

van Klaveren, Sjors LU ; Hassan, Mujtaba LU ; Håkansson, Maria LU ; Johnsson, Richard E. LU ; Larsson, Jessica LU ; Jakopin, Žiga ; Anderluh, Marko LU ; Leffler, Hakon LU ; Tomašič, Tihomir and Nilsson, Ulf J. LU (2024) In ACS Medicinal Chemistry Letters 15(8). p.1319-1324
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 Kd 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... (More)

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 Kd 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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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ADME, Galectin-8, Glycomimetic, Phthalazinone, X-ray
in
ACS Medicinal Chemistry Letters
volume
15
issue
8
pages
6 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85199255752
  • pmid:39140038
ISSN
1948-5875
DOI
10.1021/acsmedchemlett.4c00212
language
English
LU publication?
yes
id
37fd70da-ce3d-436d-a3ae-15168b82b649
date added to LUP
2024-08-01 17:45:48
date last changed
2024-08-19 08:00:43
@article{37fd70da-ce3d-436d-a3ae-15168b82b649,
  abstract     = {{<p>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<sub>d</sub> for galectin-8N (N-terminal CRD), no binding to galectin-8C (C-terminal CRD), -1, -3, -4N, -7, -9C, or -9N, and &gt;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.</p>}},
  author       = {{van Klaveren, Sjors and Hassan, Mujtaba and Håkansson, Maria and Johnsson, Richard E. and Larsson, Jessica and Jakopin, Žiga and Anderluh, Marko and Leffler, Hakon and Tomašič, Tihomir and Nilsson, Ulf J.}},
  issn         = {{1948-5875}},
  keywords     = {{ADME; Galectin-8; Glycomimetic; Phthalazinone; X-ray}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{1319--1324}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Medicinal Chemistry Letters}},
  title        = {{Galectin-8N-Selective 4-Halophenylphthalazinone-Galactals Double π-Stack in a Unique Pocket}},
  url          = {{http://dx.doi.org/10.1021/acsmedchemlett.4c00212}},
  doi          = {{10.1021/acsmedchemlett.4c00212}},
  volume       = {{15}},
  year         = {{2024}},
}