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Advancing drug discovery through assay development: a survey of tool compounds within the human solute carrier superfamily.

ABSTRACT: With over 450 genes, solute carriers (SLCs) constitute the largest transporter superfamily responsible for the uptake and efflux of nutrients, metabolites, and xenobiotics in human cells. SLCs are associated with a wide variety of human diseases, including cancer, diabetes, and metabolic and neurological disorders. They represent an important therapeutic target class that remains only partly exploited as therapeutics that target SLCs are scarce. Additionally, many small molecules reported in the literature to target SLCs are poorly characterized. Both features may be due to the difficulty of developing SLC transport assays that fulfill the quality criteria for high-throughput screening. Here, we report one of the main limitations hampering assay development within the RESOLUTE consortium: the lack of a resource providing high-quality information on SLC tool compounds. To address this, we provide a systematic annotation of tool compounds targeting SLCs. We first provide an overview on RESOLUTE assays. Next, we present a list of SLC-targeting compounds collected from the literature and public databases; we found that most data sources lacked specificity data. Finally, we report on experimental tests of 19 selected compounds against a panel of 13 SLCs from seven different families. Except for a few inhibitors, which were active on unrelated SLCs, the tested inhibitors demonstrated high selectivity for their reported targets. To make this knowledge easily accessible to the scientific community, we created an interactive dashboard displaying the collected data in the RESOLUTE web portal (https://re-solute.eu). We anticipate that our open-access resources on assays and compounds will support the development of future drug discovery campaigns for SLCs.

SUBMITTER: Digles D

PROVIDER: S-EPMC11267547 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Advancing drug discovery through assay development: a survey of tool compounds within the human solute carrier superfamily.

Digles Daniela D Ingles-Prieto Alvaro A Dvorak Vojtech V Mocking Tamara A M TAM Goldmann Ulrich U Garofoli Andrea A Homan Evert J EJ Di Silvio Alberto A Azzollini Lucia L Sassone Francesca F Fogazza Mario M Bärenz Felix F Pommereau Antje A Zuschlag Yasmin Y Ooms Jasper F JF Tranberg-Jensen Jeppe J Hansen Jesper S JS Stanka Josefina J Sijben Hubert J HJ Batoulis Helena H Bender Eckhard E Martini Riccardo R IJzerman Adriaan P AP Sauer David B DB Heitman Laura H LH Manolova Vania V Reinhardt Juergen J Ehrmann Alexander A Leippe Philipp P Ecker Gerhard F GF Huber Kilian V M KVM Licher Thomas T Scarabottolo Lia L Wiedmer Tabea T Superti-Furga Giulio G

Frontiers in pharmacology 20240709

With over 450 genes, solute carriers (SLCs) constitute the largest transporter superfamily responsible for the uptake and efflux of nutrients, metabolites, and xenobiotics in human cells. SLCs are associated with a wide variety of human diseases, including cancer, diabetes, and metabolic and neurological disorders. They represent an important therapeutic target class that remains only partly exploited as therapeutics that target SLCs are scarce. Additionally, many small molecules reported in the ...[more]

PMID: 39050757

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Project description:The human solute carrier (SLC) superfamily of transporters is comprised of over 400 membrane-bound proteins, and plays essential roles in a multitude of physiological and pharmacological processes. In addition, perturbation of SLC transporter function underlies numerous human diseases, which renders SLC transporters attractive drug targets. Common genetic polymorphisms in SLC genes have been associated with inter-individual differences in drug efficacy and toxicity. However, despite their tremendous clinical relevance, epidemiological data of these variants are mostly derived from heterogeneous cohorts of small sample size and the genetic SLC landscape beyond these common variants has not been comprehensively assessed. In this study, we analyzed Next-Generation Sequencing data from 141,456 individuals from seven major human populations to evaluate genetic variability, its functional consequences, and ethnogeographic patterns across the entire SLC superfamily of transporters. Importantly, of the 204,287 exonic single-nucleotide variants (SNVs) which we identified, 99.8% were present in less than 1% of analyzed alleles. Comprehensive computational analyses using 13 partially orthogonal algorithms that predict the functional impact of genetic variations based on sequence information, evolutionary conservation, structural considerations, and functional genomics data revealed that each individual genome harbors 29.7 variants with putative functional effects, of which rare variants account for 18%. Inter-ethnic variability was found to be extensive, and 83% of deleterious SLC variants were only identified in a single population. Interestingly, population-specific carrier frequencies of loss-of-function variants in SLC genes associated with recessive Mendelian disease recapitulated the ethnogeographic variation of the corresponding disorders, including cystinuria in Jewish individuals, type II citrullinemia in East Asians, and lysinuric protein intolerance in Finns, thus providing a powerful resource for clinical geneticists to inform about population-specific prevalence and allelic composition of Mendelian SLC diseases. In summary, we present the most comprehensive data set of SLC variability published to date, which can provide insights into inter-individual differences in SLC transporter function and guide the optimization of population-specific genotyping strategies in the bourgeoning fields of personalized medicine and precision public health.

Dataset Information

Advancing drug discovery through assay development: a survey of tool compounds within the human solute carrier superfamily.

Publications

Advancing drug discovery through assay development: a survey of tool compounds within the human solute carrier superfamily.

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