Heat Shock Protein 90 Inhibitors: An Update on Achievements, Challenges, and Future Directions

Li Li; Lei Wang; Qi-Dong You; Xiao-Li Xu

doi:10.1021/acs.jmedchem.9b00940

Heat Shock Protein 90 Inhibitors: An Update on Achievements, Challenges, and Future Directions

J Med Chem. 2020 Mar 12;63(5):1798-1822. doi: 10.1021/acs.jmedchem.9b00940. Epub 2019 Nov 12.

Authors

Li Li^{1

2}, Lei Wang^{1

2}, Qi-Dong You^{1

2}, Xiao-Li Xu^{1

2}

Affiliations

¹ State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
² Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

PMID: 31663736
DOI: 10.1021/acs.jmedchem.9b00940

Abstract

Hsp90 is one of the most important chaperones involved in regulating the maturation of more than 300 client proteins, many of which are closely associated with refractory diseases, including cancer, neurodegenerative diseases, and viral infections. Clinical Hsp90 inhibitors bind to the ATP pocket in the N-terminal domain of Hsp90 and subsequently suppress the ATPase activity of Hsp90. Recently, with the increased understanding of the discrepancies in the isoforms of Hsp90 and the modes of Hsp90-co-chaperone-client complex interactions, some new strategies for Hsp90 inhibition have emerged. Novel Hsp90 inhibitors that offer selective suppression of Hsp90 isoforms or specific disruption of Hsp90-co-chaperone protein-protein interactions are expected to show with satisfactory efficacy and safety profiles. This review summarizes the recent progress in Hsp90 inhibitors. Additionally, Hsp90 inhibitory strategies are emphasized in this review.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Autoimmune Diseases / drug therapy
Autoimmune Diseases / metabolism
Benzoquinones / chemistry
Benzoquinones / pharmacology
Benzoquinones / therapeutic use
Forecasting
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / chemistry
HSP90 Heat-Shock Proteins / metabolism*
Humans
Immunosuppressive Agents / chemistry
Immunosuppressive Agents / pharmacology
Immunosuppressive Agents / therapeutic use
Lactams, Macrocyclic / chemistry
Lactams, Macrocyclic / pharmacology
Lactams, Macrocyclic / therapeutic use
Molecular Chaperones / pharmacology
Molecular Chaperones / therapeutic use
Neoplasms / drug therapy
Neoplasms / metabolism
Protein Binding / physiology
Protein Structure, Secondary
Protein Structure, Tertiary

Substances

Antineoplastic Agents
Benzoquinones
HSP90 Heat-Shock Proteins
Immunosuppressive Agents
Lactams, Macrocyclic
Molecular Chaperones
17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
geldanamycin