Exploiting the co-reliance of tumours upon transport of amino acids and lactate: Gln and Tyr conjugates of MCT1 inhibitors

Abstract

Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an amino acid transporter recognition element was shown to augment anti-tumour efficacy vs. Raji cells. Amino acid conjugation also improves the pharmacodynamic properties of experimental MCT1/2 inhibitors.

Hypoxia and cellular metabolism in tumour pathophysiology

“…Finally, glutamine‐ and tyrosine‐based AA conjugates of monocarboxylate transporter (MCT) 1 and 2 inhibitors improved their anti‐tumour efficacy (Nair et al . ). Combined, these studies confirm the possibility of generating anticancer molecules as specific substrates for certain AA transporters thus promoting their therapeutic activity in tumours.…”

Indole Derivatives as New Structural Class of Potent and Antiproliferative Inhibitors of Monocarboxylate Transporter 1 (MCT1; SLC16A1)

“…In our study, we provided important SARs of indole derivatives and, thus, explored these as a novel molecular–structural class of MCT1 inhibitors. We obtained compounds with higher inhibitory potency compared to a significant fraction of the ∼100 reported MCT1 inhibitors in the literature, − including pteridine derivatives, most coumarin derivatives, and many cinnamic acid derivatives including reference compound 8 . ,, Nevertheless, many earlier reported MCT1 inhibitors have demonstrated inhibition concentrations significantly below the determined IC 50 values as found within our work, including thieno­[2,3- d ]­pyrimidin-2,4-diones, , pyrrolo­[3,4- d ]­pyridazinones, or 7 as well as many cinnamic acid derivatives. , However, three aspects have to be considered to put the bioactivity profile of indole derivatives into the right perspective: As MCT1 inhibitors are barely known with only roughly 100 representatives in the literature, − no standardized assay procedures have been developed compared to methodologically better-explored protein (super)­families, as, for example, ABC transporters. ,,− ,,, This led to rather diverse assay setups with a minor number of independent confirmatory studies to determine functional compound bioactivities, limiting the overall comparability of data. These diverse assays included nonfunctional MTT-based cell viability assays, ,, pH-dependent functional fluorescence assays, functional radiotracer assays [ e.g.…”

“…However, the discovery is only the first of multiple steps to access these discovered targets for pharmacotherapy. MCT1 has been described as a critical factor of cancer survival for several years now, ,− and yet, the fund of compounds addressing this SLC transporter with sufficient efficacy and preferable pharmacological profile is highly limited. − Only roughly 100 compounds have been described to address this underexplored drug target, − including the drugs and druglike compounds that were the first ligands with poor inhibitory activity, such as 1 and 3 . Potent MCT1 inhibitors with affinities in the single-digit nanomolar concentration range or even at subnanomolar concentrations indeed exist; ,,,, however, these compounds exclusively belong to the few known molecular–structural classes, as outlined in the Introduction section, and do not contribute to structural diversity.…”

“…The number of MCT1-targeting agents is rather slim, and their structural diversity is highly limited . Until today, only roughly 100 compounds are known to interact with MCT1. − Certain drugs and druglike compounds have been reported to inhibit MCT1, ,, such as benzbromarone ( 1 ) and quercetin ( 2 ), however, with rather low potency. Amongst the high-throughput screening-(HTS)- and organic synthesis-derived compounds, only a few structurally distinctive compound classes can be differentiated: (i) thieno­[2,3- d ]­pyrimidin-2,4-diones, ,− [ e.g.…”

“…, AZD-3965 ( 3 )], pteridine derivatives ,, ( e.g. , compound 4 ), pyrrolo­[3,4- d ]­pyridazinones ,, ( e.g. , compound 5 ), coumarin derivatives ,, [ e.g.…”