Digles, Daniela, Ingles-Prieto, Alvaro, Dvorak, Vojtech, Mocking, Tamara, Goldmann, Ulrich, Garofoli, Andrea, homan, Evert, Leippe, Philipp, Di Silvio, Alberto, Azzollini, Lucia, Sassone, Francesca, Forgazza, Mario, Bearenz, Felix, Pommereau, Antje, Zuschlag, Yasmin, Ooms, Jasper, Transberg-jensen, Jeppe, Hansen, Jesper, Stanka, Josefina, Jijben, Hubert, Batoulis, Helena, Bender, Eckert, Martini, Riccardo, Sosnin, Sergey, Ilzerman, Adriaan, Sauer, David, Heitman, Laura, Manolova, Vania, Reinhardt, Juergen, Ehrmann, Alexander, Ecker, Gerhard, Widmer, Tabea, Huber, Kilian, Licher, Thomas, Scarabottolo, lia and Superti-Furga, Giulio (2024) Advancing drug discovery through assay development: a survey of tool compounds within the human solute carrier superfamily. Frontiers in pharmacology, 15 (15). pp. 1-16. ISSN 1663-9812

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 openaccess
resources on assays and compounds will support the development of future
drug discovery campaigns for SLCs.

Item Type:	Article
Date Deposited:	24 Jul 2024 00:46
Last Modified:	24 Jul 2024 00:46
URI:	https://oak.novartis.com/id/eprint/52471