Monocarboxylate transporter 1 and 4 inhibitors as potential therapeutics for treating solid tumours: A review with structure-activity relationship insights

Development of multidrug resistance (MDR) is one of the major causes leading to failure of Cancer chemotherapy and radiotherapy. Monocarboxylate transporters (MCTs) MCT1 and MCT4, which are overexpressed in solid tumours, play a very important role in Cancer cell survival and proliferation. These lactate transporters work complimentarily to drive lactate shuttle in tumour cells, which results in maintenance of H⁺ ion (pH) balance necessary for their survival. Inhibition of these transmembrane proteins has been demonstrated as a novel strategy to treat drug resistant solid cancers. Presently, only a few small molecule MCT1 inhibitors such as AZD3965 and AR-C155858 are known with clinical potential. Even lesser mention of MCT4 inhibitors, which include molecules having scaffolds such as pyrazole and indazole, is available in the literature. Current overview presents the status of recent developments undertaken in identification of efficacious MCT1 and/or MCT4 inhibitors as a potential Anticancer therapy overcoming MDR. Further, detailed structure-activity relationships for different classes of compounds has been proposed to streamline the understandings learnt from ongoing research work. Through this review, we aim to highlight the importance of these excellent targets and facilitate future development of selective, potent and safe MCT1 and/or MCT4 inhibitors as promising chemotherapy for drug resistant Cancer.

Cancer; Hypoxia; Monocarboxylate transporter 1 (MCT1); Monocarboxylate transporter 4 (MCT4); Multidrug resistance.