The Development of Hsp90β-Selective Inhibitors to Overcome Detriments Associated with pan-Hsp90 Inhibition.

Abstract

The 90 kD heat shock proteins (Hsp90) are molecular chaperones that are responsible for the folding of select proteins, many of which are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials for the treatment of cancer, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms, which may lead to adverse effects. The development of Hsp90 isoform-selective inhibitors represents an alternative approach toward the treatment of cancer and may limit some of these detriments. Described herein, is a structure-based approach to develop isoform-selective inhibitors of Hsp90β, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90β-selective inhibitors as a method for overcoming the detriments associated with pan-inhibition.

• Authors: Sanket J Mishra, Weiya Liu, Kristin Beebe, Monimoy Banerjee, Caitlin N Kent, Vitumbiko Munthali, John Koren 3rd, John A Taylor 3rd, Leonard M Neckers, Jeffrey Holzbeierlein, Brian S J Blagg
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 3 Pg. 1545-1557 (02 11 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 33428418 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Heterocyclic Compounds, 4 or More Rings
• SNX 2112
• Small Molecule Libraries

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Gene Silencing
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, genetics)
• Heterocyclic Compounds, 4 or More Rings (chemistry, pharmacology)
• Humans
• Models, Molecular
• Molecular Conformation
• Neoplasms (drug therapy)
• Protein Folding
• Small Molecule Libraries
• Structure-Activity Relationship
• Substrate Specificity
• Urinary Bladder Neoplasms (drug therapy)