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Discovery of Select...
Discovery of Selective and Orally Available Galectin-1 Inhibitors
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- Zetterberg, Fredrik R (author)
- Galecto Biotech AB, Sweden
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- Diehl, Carl (author)
- SARomics Biostructures AB
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- Håkansson, Maria (author)
- SARomics Biostructures AB
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- Kahl-Knutson, Barbro (author)
- Lund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine
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- Leffler, Hakon (author)
- Lund University,Lunds universitet,Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG,Institutionen för laboratoriemedicin,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Division of Microbiology, Immunology and Glycobiology - MIG,Department of Laboratory Medicine,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Nilsson, Ulf J (author)
- Lund University,Lunds universitet,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH,Galecto Biotech AB, Sweden
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- Peterson, Kristoffer (author)
- Galecto Biotech AB, Sweden
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- Roper, James A (author)
- Stevenage Bioscience Catalyst
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- Slack, Robert J (author)
- Stevenage Bioscience Catalyst
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(creator_code:org_t)
- 2023
- 2023
- English.
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In: Journal of Medicinal Chemistry. - 1520-4804. ; 66:24, s. 16980-16990
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Abstract
Subject headings
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- A new series of orally available α-d-galactopyranosides with high affinity and specificity toward galectin-1 have been discovered. High affinity and specificity were achieved by changing six-membered aryl-triazolyl substituents in a series of recently published galectin-3-selective α-d-thiogalactosides (e.g., GB1107 Kd galectin-1/3 3.7/0.037 μM) for five-membered heterocycles such as thiazoles. The in vitro pharmacokinetic properties were optimized, resulting in several galectin-1 inhibitors with favorable properties. One compound, GB1490 (Kd galectin-1/3 0.4/2.7 μM), was selected for further characterization toward a panel of galectins showing a selectivity of 6- to 320-fold dependent on galectin. The X-ray structure of GB1490 bound to galectin-1 reveals the compound bound in a single conformation in the carbohydrate binding site. GB1490 was shown to reverse galectin-1-induced apoptosis of Jurkat cells at low μM concentrations. No cell cytotoxicity was observed for GB1490 up to 90 μM in the A549 cells. In pharmacokinetic studies in mice, GB1490 showed high oral bioavailability (F% > 99%).
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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