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

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.