title: 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 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."
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, South Korea;
authors.forename: Misook
authors.initials: M
authors.lastname: Oh
authors.affiliation: Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, South Korea;
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Molecular Biosciences and Centre for Bioinformatics, The University of Kansas, Lawrence, KS 66047; and.
authors.forename: Hui Sun
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, South Korea;
authors.forename: Woo Sirl
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202.
authors.forename: Christopher
authors.initials: C
authors.lastname: Burlak
authors.affiliation: Department of Molecular Biosciences and Centre for Bioinformatics, The University of Kansas, Lawrence, KS 66047; and.
authors.forename: Wonpil
authors.initials: W
authors.lastname: Im
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; hslim@postech.ac.kr qqhoang@iu.edu.
authors.forename: Quyen Q
authors.initials: QQ
authors.lastname: Hoang
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202;Department of Chemistry, Pohang University of Science and Technology, Pohang 790-784, South Korea; hslim@postech.ac.kr qqhoang@iu.edu.
authors.forename: Hyun-Suk
authors.initials: HS
authors.lastname: Lim
mesh_terms: D055808:Drug Discovery; D006801:Humans; D019169:Jurkat Cells; D018832:Molecular Chaperones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C579095:MCL1 protein, human; D018832:Molecular Chaperones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051844:alpha-Synuclein
keywords: chemical biology; drug discovery; helical mimetic