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Discovery of 5-{2-[5-Chloro-2-(5-ethoxyquinoline-8-sulfonamido)phenyl]ethynyl}-4-methoxypyridine-2-carboxylic Acid, a Highly Selective in Vivo Useable Chemical Probe to Dissect MCT4 Biology.
- Source :
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Journal of medicinal chemistry [J Med Chem] 2021 Aug 26; Vol. 64 (16), pp. 11904-11933. Date of Electronic Publication: 2021 Aug 12. - Publication Year :
- 2021
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Abstract
- Due to increased lactate production during glucose metabolism, tumor cells heavily rely on efficient lactate transport to avoid intracellular lactate accumulation and acidification. Monocarboxylate transporter 4 (MCT4/SLC16A3) is a lactate transporter that plays a central role in tumor pH modulation. The discovery and optimization of a novel class of MCT4 inhibitors (hit 9a ), identified by a cellular screening in MDA-MB-231, is described. Direct target interaction of the optimized compound 18n with the cytosolic domain of MCT4 was shown after solubilization of the GFP-tagged transporter by fluorescence cross-correlation spectroscopy and microscopic studies. In vitro treatment with 18n resulted in lactate efflux inhibition and reduction of cellular viability in MCT4 high expressing cells. Moreover, pharmacokinetic properties of 18n allowed assessment of lactate modulation and antitumor activity in a mouse tumor model. Thus, 18n represents a valuable tool for investigating selective MCT4 inhibition and its effect on tumor biology.
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents pharmacology
Cell Line, Tumor
Drug Screening Assays, Antitumor
Female
HEK293 Cells
Humans
Lactic Acid metabolism
Mice, Inbred C57BL
Mice, Nude
Mice, SCID
Molecular Structure
Picolinic Acids chemical synthesis
Picolinic Acids pharmacology
Structure-Activity Relationship
Sulfonamides chemical synthesis
Sulfonamides pharmacology
Xenograft Model Antitumor Assays
Mice
Antineoplastic Agents therapeutic use
Monocarboxylic Acid Transporters antagonists & inhibitors
Muscle Proteins antagonists & inhibitors
Neoplasms drug therapy
Picolinic Acids therapeutic use
Sulfonamides therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34382802
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00448