Identification of the mechanism of action of CYT-0851, an inhibitor of monocarboxylate transporter (MCT) mediated lactate transport

CYT-0851 was discovered using a phenotypic screen and rapidly advanced to phase 1 clinical trial where responses in solid tumor lymphoma patients have been observed. To elucidate the mechanism of action (MOA) CYT-0851, extensive bioinformatic, functional genomic, molecular characterization performed. This preclinical work demonstrated that disrupts lactate transport via inhibition monocarboxylate transporter (MCT) activity. In proliferating cancers, is produced during glycolysis exported primarily by MCT1 MCT4, which provide redundancy when co-expressed. Methods: sensitivity data across 439 cell lines cross-compared with available DepMap gene essentiality expression data. A genome-wide CRISPR identified genes significantly influenced CYT-0851. MDCKII cells expressing human were treated substrate, 2-thiophene-glyoxylic acid, quantified LC-MS. CYT-0851-mediated reversal cytotoxicity induced 3-bromopyruvate, an measured Daudi cells. Lactate Lactate-Glo. Extracellular acidification O2 consumption Seahorse. Results: Bioinformatic analysis revealed treatment most closely phenocopied genetic loss effective at inhibiting growth low MCT4 expression. dropout consistently genomic as significant sensitizer dose-dependently inhibited activity IC50 134 nM protected from cytotoxic effects 3-bromopyruvate. Intracellular levels increased strongly correlated 10 lines. metabolic shift mitochondrial respiration reduced extracellular rate consumption. enhanced inhibitors oxidative phosphorylation. Additional orthogonal studies validating completed. Conclusions: Rapidly cancers rely on lactate-producing necessitates export through MCTs. MCT-mediated glycolytic cancer results intracellular accumulation, disruption cellular metabolism energetics, cytotoxicity. Given highly nature many MCTs are attractive target for therapies. 1/2 monotherapy combination chemotherapy. Translational analyses patient samples ongoing confirm pharmacodynamic consistent MOA test predictive biomarker hypotheses. Conflict interest: Ownership: Cyteir Therapeutics