Galectin-8N-Selective 4-Halophenylphthalazinone-Galactals Double π-Stack in a Unique Pocket
(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
- 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
- organization
- publishing date
- 2024
- 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 >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}}, }