Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery

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.…”

“…(i) As MCT1 inhibitors are barely known with only roughly 100 representatives in the literature, 18−31 no standardized assay procedures have been developed compared to methodologically better-explored protein (super)families, as, for example, ABC transporters. 2,7,[52][53][54][55][56][57][58][59][60][61]63,66,72 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, 21,25,33 pH-dependent functional fluorescence assays, 34 functional radiotracer assays [e.g., 3 H-labeling of test candidates, 34 14 C-labeling of MCT1 substrates ( 14 C-lactate 21,22,24,25,31,33,34 ), or photoaffinity labeling (e.g., by 125 I-labeling 29 )]�often focusing on binding a ffi n i t y 2 9 , 3 4 r a t h e r t h a n i n h i b i t o r y p o w e r (IC 50 ).…”

“…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.…”

“…3-BP, on the other hand, is a regular chemical without regulatory constraints, promoting general use; (b) radiotracer assays are accompanied—apart from regulatory constraints—by complex protocols, which makes the determination of full-blown concentration-effect curves or even high-throughput screenings a challenge. In contrast, the 3-BP assay is an easy-to-perform assay with a protocol comparable to other functional and/or MTT-based assays as described for other protein (super)families, as, for example, ABC transporters; 2 , 7 , 52 − 61 , 63 , 66 , 72 and (c) furthermore, the 3-BP assay demonstrated extreme reliability and robustness, as can be seen from the low deviations depicted either in Table 1 as well as in Figure 3 .…”

“…However, first- and even second-line anticancer drugs become often ineffective due to the occurrence of multidrug resistance (MDR) of cancer cells, by either mutations/changed drug targets or reduced drug uptake/upregulation of efflux transporters, ,, amongst other reasons. Although tremendous advances have been made within the last two decades by the discovery of novel anticancer drug targets, ,− the frequent occurrence of MDR forces research to focus on new pharmacological targets for the exploration of novel cancer drug targets of the future.…”