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HSP90 Inhibitors Blocking Multiple Oncogenic Signaling Pathways for the Treatment of Cancer

  • Fen Jiang
  • Xiao-Li Xu
  • Qi-Dong YouEmail author
Chapter
Part of the Heat Shock Proteins book series (HESP, volume 17)

Abstract

Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone which plays important roles in the development of cancer. Inhibition of the HSP90 chaperone function can disrupt multiple cancer dependent signaling pathways and result in potent anti-cancer effects, which has been a promising anti-cancer strategy. Up to now, HSP90 inhibitors with different mechanisms have been developed, including HSP90 N-terminal inhibitors (pan-isoform and isoform selective), C-terminal inhibitors and HSP90-cochaperone protein-protein interaction (PPI) inhibitors. In this chapter, we will review the current development of HSP90 inhibitors as anti-cancer agents.

Keywords

Cancer GRP94 HSP90-CDC37 PPI HSP90 inhibitor Isoform selective TRAP1 

Abbreviations

BTZ

bortezomib

CR

complete response

CTD

C-terminal domain

DHPM

3,4-dihydropyrimidin-2-(1H)-one

DLTs

dose-limiting toxicities

EGCG

epigallocatechin gallate

ER

endoplasmic reticulum

ESCC

esophageal squamous cell carcinoma

FU

5-fluorouracil

GRP94

glucose-regulated protein 94

HGF

hepatocyte growth factor

HSP

Heat shock protein

HTRF

homogeneous time-resolved fluorescence

IGFs

insulin-like growth factors

IRI

irinotecan

l-OHP

oxaliplatin

MD

middle-domain

MM

multiple myeloma

MTD

maximum tolerance dose

NSCLC

non-small cell lung cancer

NTD

N-terminal domain

PPI

protein-protein interaction

PR

partial response

RDA

radamide

SD

stable disease

SDH

succinate dehydrogenase

SPR

surface plasmon resonance

TEAEs

treatment-related adverse events

TRAIL

TNF-α–related apoptosis-inducing ligand

TRAMP

transgenic adenocarcinoma of the mouse prostate

TRAP1

tumor necrosis factor receptor-associated protein-1

Notes

Acknowledgements

This work is supported by Projects 81872737 and 81773639 of the National Natural Science Foundation of China; 2632018ZD15 of the Key Program of China Pharmaceutical University; 2017ZX0-9302003, and 2018ZX09711002-003-006 of the National Major Science and Technology Project of China (Innovation and Development of New Drugs).

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, School of PharmacyChina Pharmaceutical UniversityNanjingChina

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