2. Academic Validation
  3. 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

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 Aug 26;64(16):11904-11933. doi: 10.1021/acs.jmedchem.1c00448.
Timo Heinrich 1,  Ada Sala-Hojman 1,  Roberta Ferretti 2,  Carl Petersson 1,  Stefano Minguzzi 3,  Andrzej Gondela 4,  Shivapriya Ramaswamy 2,  Anna Bartosik 4,  Frank Czauderna 2,  Lindsey Crowley 2,  Pamela Wahra 2,  Heike Schilke 1,  Pia Böpple 1,  Łukasz Dudek 4,  Marcin Leś 4,  Paulina Niedziejko 4,  Kamila Olech 4,  Henryk Pawlik 4,  Łukasz Włoszczak 4,  Karol Zuchowicz 4,  Jose Ramon Suarez Alvarez 4,  Justyna Martyka 4,  Ewa Sitek 4,  Maciej Mikulski 4,  Joanna Szczęśniak 4,  Sven Jäckel 1,  Mireille Krier 1,  Marcin Król 4,  Ansgar Wegener 1,  Michał Gałęzowski 4,  Mateusz Nowak 4,  Frank Becker 3,  Christian Herhaus 1
Affiliations

Affiliations

  • 1 Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
  • 2 EMD Serono Research & Development Institute, Inc., 45A Middlesex Turnpike, Billerica, Massachusetts 01821, United States.
  • 3 Intana, Bioscience GmbH, Lochhamer Str. 29a, 82152 Planegg, Martinsried, Germany.
  • 4 Ryvu Therapeutics, Sternbacha 2, 30-394 Kraków, Poland.
PMID: 34382802 DOI: 10.1021/acs.jmedchem.1c00448
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.

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