Potential pharmacological chaperones targeting cancer-associated MCL-1 and Parkinson disease-associated α-synuclein

Abstract

Pharmacological chaperones are small molecules that bind to proteins and stabilize them against thermal denaturation or proteolytic degradation, as well as assist or prevent certain protein-protein assemblies. These activities are being exploited for the development of treatments for diseases caused by protein instability and/or aberrant protein-protein interactions, such as those found in certain forms of cancers and neurodegenerative diseases. However, designing or discovering pharmacological chaperones for specific targets is challenging because of the relatively featureless protein target surfaces, the lack of suitable chemical libraries, and the shortage of efficient highthroughput screening methods. In this study, we attempted to address all these challenges by synthesizing a diverse library of small molecules that mimic protein α-helical secondary structures commonly found in protein-protein interaction surfaces. This was accompanied by establishing a facile "on-bead" high-throughput screening method that allows for rapid and efficient discovery of potential pharmacological chaperones and for identifying novel chaperones/ inhibitors against a cancer-associated protein, myeloid cell leukemia 1 (MCL-1), and a Parkinson disease-associated protein, α-synuclein. Our data suggest that the compounds and methods described here will be useful tools for the development of pharmaceuticals for complexdisease targets that are traditionally deemed "undruggable." chemical biology | drug discovery | helical mimetic

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

“…Noteworthy, a recent study introduced a novel high-throughput method for the identification of pharmacological chaperones, particularly those related to protein-protein interactions. The investigators were able to generate a novel compound library enriched with pharmacological chaperones, which could potentially obviate the need to predetermine the 3D structure of a targeted protein, relying on the observation that short α-helical peptide segments, spanning 2-3 helical turns, often play key roles in proteinprotein interactions [18]. Most of the work up to now has been focused on chaperoning unstable mutant proteins, but there is no reason, in principle, to use chaperones to stabilize the normal form of a protein and thereby increasing its steadystate cellular levels, as we have done with the mammalian retromer complex.…”

Selective and Potent Proteomimetic Inhibitors of Intracellular Protein–Protein Interactions

“…Such ligands have been termed proteomimetics,18 α‐helix mimetics,19–22 and topographical mimics 23. Several studies on this general class of ligand have illustrated that they can be used to selectively recognize their target protein in biophysical assays,19, 24, 25 that they act in cells upon the pathway in which the PPI is found,23, 26, 27, 52 and that they exhibit the anticipated phenotypic effects in animals 23. In this work we performed biophysical and cellular experiments on a library of N‐alkylated aromatic oligoamide proteomimetics (Figure 1).…”

Pharmacological chaperones in the age of proteomic pathology

“…6 and 7). However, since the concept of pharmacological chaperones was introduced just over a decade ago (8), a number of technical barriers have hindered their wide-scale application and utility in drug discovery. The paper by Oh et al (8) in PNAS sets out to tackle some of these barriers head on.…”

“…Providing proof-of-principle, Oh et al (8) then applied this library to isolate putative pharmacological chaperones directed against proteins thought to play pathogenic roles in either cancer or in Parkinson disease. Myeloid cell leukemia-1 (MCL-1) is a protein that is apparently thought to play a role in cancer progression by binding members of the B-cell lymphoma-2 homology domain-3 family of proteins.…”

“…Next, Oh et al screened their library and successfully identified small molecules that reduced the aggregation of the protein α-synuclein, aggregates that are thought to play a pathogenic role in Parkinson disease. As the authors admit, it remains unknown whether the putative small molecule binding to α-synuclein "prevented it from aggregating, either by masking the surfaces that directly involve in aggregation or by preventing its conversion/misfolding into aggregation prone species" (8).…”