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@ARTICLE{Bickel:864930,
author = {Bickel, David and Gohlke, Holger},
title = {{C}-terminal {M}odulators of {H}eat {S}hock {P}rotein of 90
k{D}a ({HSP}90): {S}tate of {D}evelopment and {M}odes of
{A}ction},
journal = {Bioorganic $\&$ medicinal chemistry},
volume = {27},
number = {21},
issn = {0968-0896},
address = {Amsterdam [u.a.]},
publisher = {Elsevier},
reportid = {FZJ-2019-04533},
pages = {115080},
year = {2019},
abstract = {Cells constantly need to adopt to changing environmental
conditions, maintaining homeostasis and proteostasis. Heat
shock proteins are a diverse class of molecular chaperones
that assist proteins in folding to prevent stress-induced
misfolding and aggregation. The heat shock protein of 90 kDa
(HSP90) is the most abundant heat shock protein. While basal
expression of HSP90 is essential for cell survival, in many
tumors elevated HSP90 levels are found, which is often
associated with bad prognosis. Therefore, HSP90 has emerged
as a major target in tumor therapy. The HSP90 machinery is
very complex in that it involves large conformational
changes during the chaperoning cycle and a variety of
co-chaperones. At the same time, this complexity offers a
plethora of possibilities to interfere with HSP90 function.
The best characterized class of HSP90 modulators are
competitive inhibitors targeting the N-terminal ATP-binding
pocket. Nineteen compounds of this class entered clinical
trials. However, due to severe adverse effects, including
induction of the heat shock response, no N-terminal
inhibitor has been approved by the FDA so far. As
alternatives, compounds commonly referred to as
“C-terminal inhibitors” have been developed, either as
natural product-based analogues or by rational design, which
employ multiple mechanisms to modulate HSP90 function,
including modulation of the interaction with co-chaperones,
induction of conformational changes that influence the
chaperoning cycle, or inhibition of C-terminal dimerization.
In this review, we summarize the current development state
of characteristic C-terminal inhibitors, with an emphasis on
their (proposed) molecular modes of action and binding
sites.},
cin = {JSC / NIC / ICS-6},
ddc = {610},
cid = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)NIC-20090406 /
I:(DE-Juel1)ICS-6-20110106},
pnm = {511 - Computational Science and Mathematical Methods
(POF3-511) / Forschergruppe Gohlke $(hkf7_20170501)$},
pid = {G:(DE-HGF)POF3-511 / $G:(DE-Juel1)hkf7_20170501$},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:31519378},
UT = {WOS:000488203800001},
doi = {10.1016/j.bmc.2019.115080},
url = {https://juser.fz-juelich.de/record/864930},
}