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

Misook Oh, Ji Hoon Lee, Wei Wang, Hui Sun Lee, Woo Sirl Lee, Christopher Burlak, Wonpil Im, Quyen Q. Hoang, Hyun Suk Lim

Research output: Contribution to journalArticle

41 Scopus citations

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 high-throughput 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 complex-disease targets that are traditionally deemed "undruggable.".

Original languageEnglish (US)
Pages (from-to)11007-11012
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number30
DOIs
StatePublished - Jan 1 2014

Keywords

  • Chemical biology
  • Drug discovery
  • Helical mimetic

ASJC Scopus subject areas

  • General

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