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

• Published in: Journal of medicinal chemistry Vol. 64; no. 16; pp. 11904 - 11933
• Main Authors: Heinrich, Timo, Sala-Hojman, Ada, Ferretti, Roberta, Petersson, Carl, Minguzzi, Stefano, Gondela, Andrzej, Ramaswamy, Shivapriya, Bartosik, Anna, Czauderna, Frank, Crowley, Lindsey, Wahra, Pamela, Schilke, Heike, Böpple, Pia, Dudek, Łukasz, Leś, Marcin, Niedziejko, Paulina, Olech, Kamila, Pawlik, Henryk, Włoszczak, Łukasz, Zuchowicz, Karol, Suarez Alvarez, Jose Ramon, Martyka, Justyna, Sitek, Ewa, Mikulski, Maciej, Szczęśniak, Joanna, Jäckel, Sven, Krier, Mireille, Król, Marcin, Wegener, Ansgar, Gałęzowski, Michał, Nowak, Mateusz, Becker, Frank, Herhaus, Christian
• Format: Journal Article
• Language: English
• Published: United States 26-08-2021
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; HEK293 Cells; Humans; Lactic Acid - metabolism; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, SCID; Molecular Structure; Monocarboxylic Acid Transporters - antagonists & inhibitors; Muscle Proteins - antagonists & inhibitors; Neoplasms - drug therapy; Picolinic Acids - chemical synthesis; Picolinic Acids - pharmacology; Picolinic Acids - therapeutic use; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00448

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
), identified by a cellular screening in MDA-MB-231, is described. Direct target interaction of the optimized compound
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
resulted in lactate efflux inhibition and reduction of cellular viability in MCT4 high expressing cells. Moreover, pharmacokinetic properties of
allowed assessment of lactate modulation and antitumor activity in a mouse tumor model. Thus,
represents a valuable tool for investigating selective MCT4 inhibition and its effect on tumor biology.