jm1c00448_si_001.pdf (3.34 MB)
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
journal contribution
posted on 2021-08-12, 14:12 authored by Timo Heinrich, Ada Sala-Hojman, Roberta Ferretti, Carl Petersson, Stefano Minguzzi, Andrzej Gondela, Shivapriya Ramaswamy, Anna Bartosik, Frank Czauderna, Lindsey Crowley, Pamela Wahra, Heike Schilke, Pia Böpple, Łukasz Dudek, Marcin Leś, Paulina Niedziejko, Kamila Olech, Henryk Pawlik, Łukasz Włoszczak, Karol Zuchowicz, Jose Ramon Suarez Alvarez, Justyna Martyka, Ewa Sitek, Maciej Mikulski, Joanna Szczęśniak, Sven Jäckel, Mireille Krier, Marcin Król, Ansgar Wegener, Michał Gałęzowski, Mateusz Nowak, Frank Becker, Christian HerhausDue
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.
