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

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