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

• Published in: Journal of medicinal chemistry 2023-01, Vol.66 (1), p.384-397
• Main Authors: Goldberg, Frederick W., Kettle, Jason G., Lamont, Gillian M., Buttar, David, Ting, Attilla K. T., McGuire, Thomas M., Cook, Calum R., Beattie, David, Morentin Gutierrez, Pablo, Kavanagh, Stefan L., Komen, Jasper C., Kawatkar, Aarti, Clark, Roger, Hopcroft, Lorna, Hughes, Gareth, Critchlow, Susan E.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Humans; Hypoxia; Lactic Acid; Monocarboxylic Acid Transporters; Neoplasms - drug therapy; Symporters
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01342

Due to increased reliance on glycolysis, which produces lactate, monocarboxylate transporters (MCTs) are often upregulated in cancer. MCT4 is associated with the export of lactic acid from cancer cells under hypoxia, so inhibition of MCT4 may lead to cytotoxic levels of intracellular lactate. In addition, tumor-derived lactate is known to be immunosuppressive, so MCT4 inhibition may be of interest for immuno-oncology. At the outset, no potent and selective MCT4 inhibitors had been reported, but a screen identified a triazolopyrimidine hit, with no close structural analogues. Minor modifications to the triazolopyrimidine were made, alongside design of a constrained linker and broad SAR exploration of the biaryl tail to improve potency, physical properties, PK, and hERG. The resulting clinical candidate 15 (AZD0095) has excellent potency (1.3 nM), MCT1 selectivity (>1000×), secondary pharmacology, clean mechanism of action, suitable properties for oral administration in the clinic, and good preclinical efficacy in combination with cediranib.