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

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.

LINC00035 Transcriptional Regulation of SLC16A3 via CEBPB Affects Glycolysis and Cell Apoptosis in Ovarian Cancer

“…SLC16A3 is greatly involved in tumor pH modulation as a lactate transporter. In a mouse tumor model, lactate modulation and anti-tumor activity were evaluated through the direct target interaction of the optimized compound 18n with the cytosolic domain of SLC16A3 suggesting pharmacokinetic inhibition of SLC16A3 by 18n is a useful outcome measure for anti-tumor effects on tumor biology [ 34 ]. Our following investigations demonstrated SLC16A3 was upregulated in OC tissues.…”

Nickel(0)-catalysed linear-selective hydroarylation of 2-aminostyrenes with arylboronic acids by a bifunctional temporary directing group strategy

“…As a comparison, treating 3a with D 2 O under standard conditions resulted in no H/D exchange at the benzylic position. 14 This result indicates that water may act as the proton source for this transformation while the phenolic OH group of L1 acts as the proton shuttle during the formation of nickel-hydride. Moreover, exclusive deuterium incorporation at the benzylic position suggests the formation of a nickel homobenzylic intermediate from migratory insertion of the alkene moiety into the nickel-hydride species, through which the overall hydroarylation reaction was achieved with linear selectivity.…”

“…This redox-neutral protocol would allow the rapid access of 2-arylethylanilines, which are present in a large number of biologically active molecules (Scheme 1D). 14 However, to realize such a transformation, the possible contamination of the nickel(0) catalyst by the free amino group and the undesired C–N coupling (Chan–Lam coupling) between aniline and arylboronic acid are the major challenges that need to be overcome. 15…”

Discovery of Clinical Candidate AZD0095, a Selective Inhibitor of Monocarboxylate Transporter 4 (MCT4) for Oncology

“…. Title compound was prepared in a similar manner to compound 4, from commercially available 5-phenyl-2-pyrazinecarboxylic acid; 1 H NMR (500 MHz, DMSO-d 6 ) 2.46 (s, 3H), 2.67 (s, 3H), 2.77 (s, 3H), 3.02 (t, J = 7.3 Hz, 2H), 3.54 (q, J = 6.9 Hz, 2H), 7.59 (d, J = 6.0 Hz, 3H), 8.25 (d, J = 5.8 Hz, 2H), 9.21 (s, 1H), 9.23 (t, 1H, NH), 9.30 (s, 1H); 13…”

“…However, at the outset of this program, no potent and selective MCT4 inhibitors had been reported in the literature, and identifying such inhibitors is challenging due to the phenotypic nature of the screening cascade for targeting a membrane transporter, although some have been reported more recently, 10−12 including a series of carboxylic acids from Ryvu/Merck KGaA. 13 Initially, the AstraZeneca compound collection was screened for acidic hits, using the rationale that natural substrates for the monocarboxylate transporters are low-molecular-weight carboxylic acids such as lactic acid and pyruvic acid. This screen used a lactate efflux assay in SKBr3 cells, with counter-screening in a lactate influx fluorometric imaging plate reader (FLIPR) assay in NCI-H358 cells to remove false positives.…”