Journal article
Discovery of novel Hsp90 C-terminal domain inhibitors that disrupt co-chaperone binding
OW Mak, N Sharma, J Reynisson, IKH Leung
Bioorganic and Medicinal Chemistry Letters | PERGAMON-ELSEVIER SCIENCE LTD | Published : 2021
Abstract
Heat shock protein 90 (Hsp90) is an essential molecular chaperone that performs vital stress-related and housekeeping functions in cells and is a current therapeutic target for diseases such as cancers. Particularly, the development of Hsp90 C-terminal domain (CTD) inhibitors is highly desirable as inhibitors that target the N-terminal nucleotide-binding domain may cause unwanted biological effects. Herein, we report on the discovery of two drug-like novel Hsp90 CTD inhibitors by using virtual screening and intrinsic protein fluorescence quenching binding assays, paving the way for future development of new therapies that employ molecular chaperone inhibitors.
Grants
Funding Acknowledgements
The plasmid GST-Hsp90 C(626-732) was a gift from William Sessa (Addgene plasmid #22483; http://n2t.net/addgene:22483; RRID: Addgene_22483).89 We thank Dr Alexander Wolf (Institute of Molecular Toxicology & Pharmacology, Helmholtz Zentrum Munich) for technical support in plasmid preparation. We thank Dr Christopher Walker (School of Biological Sciences, The University of Auckland) for providing training and technical support with the Alpha assay. Oi Wei Mak gratefully acknowledges the support of a University of Auckland Doctoral Scholarship. We thank the University of Auckland for funding. Johannes Reynisson is on the inventors' list for Luminespib, a Hsp90 inhibitor in clinical trials. All other authors declare no conflict of interest.