A Holistic Evolutionary and 3D Pharmacophore Modelling Study Provides Insights into the Metabolism, Function, and Substrate Selectivity of the Human Monocarboxylate Transporter 4 (hMCT4)

Abstract

Monocarboxylate transporters (MCTs) are of great research interest for their role in cancer cell metabolism and their potential ability to transport pharmacologically relevant compounds across the membrane. Each member of the MCT family could potentially provide novel therapeutic approaches to various diseases. The major differences among MCTs are related to each of their specific metabolic roles, their relative substrate and inhibitor affinities, the regulation of their expression, their intracellular localization, and their tissue distribution. MCT4 is the main mediator for the efflux of L-lactate produced in the cell. Thus, MCT4 maintains the glycolytic phenotype of the cancer cell by supplying the molecular resources for tumor cell proliferation and promotes the acidification of the extracellular microenvironment from the co-transport of protons. A promising therapeutic strategy in anti-cancer drug design is the selective inhibition of MCT4 for the glycolytic suppression of solid tumors. A small number of studies indicate molecules for dual inhibition of MCT1 and MCT4; however, no selective inhibitor with high-affinity for MCT4 has been identified. In this study, we attempt to approach the structural characteristics of MCT4 through an in silico pipeline for molecular modelling and pharmacophore elucidation towards the identification of specific inhibitors as a novel anti-cancer strategy.

Heterocyclic and non‐heterocyclic arena of monocarboxylate transporter inhibitors to battle tumorigenesis

“…The loss of MCT4 inhibitory action was a tradeoff for replacing the N,N-dialkyl/aryl side chain (amine linker) with the O-alkyl side chain (ether linker) to enhance the pharmacokinetic profile. These findings are indeed extremely intriguing, and additional CHC chemical modification may hold the promise of discovering MCT1 or dual MCT1/MCT4 inhibitors that are drug-like (Nelson et al, 2019).…”

“…The main drawback of MCT inhibitors is brain toxicity which leads to neurodegenerative disorders like epilepsy, cognitive defects, etc., due to the brain utilizing the lactate molecules as oxidative fuel in the presence of MCTs (Pérez-Escuredo et al, 2016). So, selectivity and specificity are kept as paramount features to overcome these kinds of adverse effects (Papakonstantinou et al, 2021). This article discusses heterocyclic and non-heterocyclic therapeutic agents (Figure 3), including their chemistry and comprehensive inhibiting potency against MCT.…”

Research Progress on Improving the Efficiency of CDT by Exacerbating Tumor Acidification

“…The acidic microenvironment is an important condition for promoting treatment of CDT. 62 At present, the main proton pumps and proteins involved in tumor pH regulation are carbonic anhydrase IX (CAIX), 63 monocarboxylate transporters (MCT), 64 Na + /H + exchanger (NHE), 65 Na + -HCO 3 − cotransporter (NBCn1) and so on, 66 and its regulation mechanism is showed in Figure 5 . These inhibitors can regulate the activity of these proton pumps and proteins to inhibit the efflux of intracellular lactate/H + and acidify the TME, which is more conducive to the occurrence of Fenton reaction.…”