Abstract

High-throughput cell-based phenotypic screens are one
of the golden standards in drug discovery. Such screens enable the testing of
large chemical compound libraries in a rapid and efficient manner. Using this
approach, the Genomic Instability group, led by Prof. Fernández-Capetillo at
the CNIO in Madrid (Spain), successfully developed an ATR kinase inhibitor with
potent anti-cancer activity¹. Building on this success, Prof.
Fernández-Capetillo has recently started a second lab, located at the
Karolinska Institutet in Stockholm (Sweden), which focusses on the use of cell
based high-throughput phenotypic screens to discover and explore novel
treatments for rare diseases, such as Amyotrophic Lateral Sclerosis (ALS) and
Huntington’s Disease (HD). To this end, we have established different cell
models mirroring some of the pathological phenotypes occurring in ALS, such as
cell death due to TDP-43 aggregation or the di-peptide repeats resulting from
the intronic hexanucleotide repeat expansion in C9ORF72. In addition, we are currently developing a cellular model
of HD in which Huntingtin containing a poly-Q repeat expansion is expressed.
Finally, we are not only working with cellular models, but also with higher
vertebrate models such as zebrafish, for which we are developing inducible ALS
and HD systems for high-throughput screening. Taking advantage of our group's
expertise in high-content microscopy screens, we are also testing different
chemical libraries in the search for compounds that are able to target
undruggable proteins related to ALS onset. Our lab is located at
the Science for Life Laboratories, which houses many national facilities,
amongst them the Laboratories for Chemical Biology at Karolinska Institutet (LCBKI),
which grants us access to up to 200,000 compound libraries, ranging from FDA
approved drugs, tool compounds with known target, to uncharacterised and
chemically diverse libraries. Using one of these chemical collections (4,126
compounds), we have recently identified compounds that can limit the toxicity
of the ALS-related PR₂₀ di-peptide². In a different context, we
have also discovered compounds that are capable of inducing the expression of
the immune-checkpoint ligand PD-L1 in a subset of breast tumors, highlighting
the robustness of our strategy as well as the broad-spectrum of applications in
which it can be applied. Our general strategy for the discovery of novel ALS
and HD therapies will be discussed.

1. Toledo
L, Murga M, Zur R et al Nat Struct
Mol Biol 2011; 18: 721-727

2. Corman A, Jung B, Häggblad M et al Cell Chem Biol 2019; 26: 235-243