RT Journal Article
T1 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
A1 Heinrich, Timo
A1 Sala-Hojman, Ada
A1 Ferretti, Roberta
A1 Petersson, Carl
A1 Minguzzi, Stefano
A1 Gondela, Andrzej
A1 Ramaswamy, Shivapriya
A1 Anna Bartosik, 
A1 Czauderna, Frank
A1 Crowley, Lindsey
A1 Wahra, Pamela
A1 Schilke, Heike
A1 Böpple, Pia
A1 Dudek, Łukasz
A1 Leś, Marcin
A1 Niedziejko, Paulina
A1 Olech, Kamila
A1 Pawlik, Henryk
A1 Włoszczak, Łukasz
A1 Zuchowicz, Karol
A1 Suárez Álvarez, José Ramón
A1 Martyka, Justyna
A1 Sitek, Ewa
A1 Mikulski, Maciej
A1 Szczęśniak, Joanna
A1 Jäckel, Sven
A1 Krier, Mireille
A1 Król, Marcin
A1 Wegener, Ansgar
A1 Gałęzowski, Michał
A1 Nowak, Mateusz
A1 Becker, Frank
A1 Herhaus, Christian
AB 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.
PB American Chemical Society
SN 0022-2623
YR 2021
FD 2021
LK https://hdl.handle.net/20.500.14352/100876
UL https://hdl.handle.net/20.500.14352/100876
LA eng
NO Heinrich T, Sala-Hojman A, Ferretti R, Petersson C, Minguzzi S, Gondela A, et al. 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. J Med Chem 2021;64:11904–33. https://doi.org/10.1021/acs.jmedchem.1c00448.
DS Docta Complutense
RD 16 abr 2025