This title appears in the Scientific Report :
2019
Please use the identifier:
http://dx.doi.org/10.1016/j.bmc.2019.115080 in citations.
Please use the identifier: http://hdl.handle.net/2128/23059 in citations.
C-terminal Modulators of Heat Shock Protein of 90 kDa (HSP90): State of Development and Modes of Action
C-terminal Modulators of Heat Shock Protein of 90 kDa (HSP90): State of Development and Modes of Action
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...
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Personal Name(s): | Bickel, David |
---|---|
Gohlke, Holger (Corresponding author) | |
Contributing Institute: |
Strukturbiochemie; ICS-6 John von Neumann - Institut für Computing; NIC Jülich Supercomputing Center; JSC |
Published in: | Bioorganic & medicinal chemistry, 27 (2019) 21, S. 115080 |
Imprint: |
Amsterdam [u.a.]
Elsevier
2019
|
DOI: |
10.1016/j.bmc.2019.115080 |
PubMed ID: |
31519378 |
Document Type: |
Journal Article |
Research Program: |
Forschergruppe Gohlke Computational Science and Mathematical Methods |
Link: |
Published on 2019-08-26. Available in OpenAccess from 2021-08-26. Published on 2019-08-26. Available in OpenAccess from 2021-08-26. |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/23059 in citations.
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. |