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Article: The Right Tool for the Job: An Overview of Hsp90 Inhibitors.

Koren, John / Blagg, Brian S J

Advances in experimental medicine and biology

2020 Volume 1243, Page(s) 135–146

Abstract: Molecular chaperones are responsible for maintaining intracellular protein quality control by facilitating the conformational maturation of new proteins as well as the refolding of denatured proteins. While there are several classes of molecular ... ...

Abstract	Molecular chaperones are responsible for maintaining intracellular protein quality control by facilitating the conformational maturation of new proteins as well as the refolding of denatured proteins. While there are several classes of molecular chaperones in the cell, this chapter will focus solely on the small molecule modulation of Hsp90, the 90 kDa heat shock protein. Hsp90 is not only responsible for folding nascent proteins, but it also regulates the triage of numerous client proteins through partnering with the ubiquitin-proteasome pathway. Consequently, Hsp90 plays critical role in maintaining the protein homeostasis (proteostasis) network within the cell and is required for the activation/maturation of more than 300 client protein substrates. Many of the clients that depend upon Hsp90 are overexpressed or mutated during malignant transformation. This often renders the clients thermodynamically unstable and dependent on Hsp90 for stability. This phenomenon results in an oncogenic 'addiction' to the Hsp90 protein folding machinery as Hsp90 maintains onco-client proteins. Furthermore, Hsp90-dependent substrates are associated with all ten hallmarks of cancer, making Hsp90 an attractive target for the development of cancer chemotherapeutics. In fact, 17 small molecule inhibitors of Hsp90 have been developed and clinically evaluated for the treatment of cancer. Unfortunately, most of these molecules have failed for various reasons, necessitating a new approach to modulate the Hsp90 protein folding machine.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; HSP90 Heat-Shock Proteins/antagonists & inhibitors ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Protein Folding/drug effects
Chemical Substances	Antineoplastic Agents ; HSP90 Heat-Shock Proteins
Language	English
Publishing date	2020-04-15
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-3-030-40204-4_9
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Article ; Online: Effects of altered tau expression on dentate granule cell excitability in mice.

Cloyd, Ryan A / Koren, John / Abisambra, Jose F / Smith, Bret N

Experimental neurology

2021 Volume 343, Page(s) 113766

Abstract: Tauopathies, including Alzheimer's disease, are characterized by progressive accumulation of hyperphosphorylated and pathologic tau protein in association with onset of cognitive and behavioral impairment. Tau pathology is also associated with increased ... ...

Abstract	Tauopathies, including Alzheimer's disease, are characterized by progressive accumulation of hyperphosphorylated and pathologic tau protein in association with onset of cognitive and behavioral impairment. Tau pathology is also associated with increased susceptibility to seizures and epilepsy, with tau
MeSH term(s)	Age Factors ; Animals ; Dentate Gyrus/cytology ; Dentate Gyrus/metabolism ; Excitatory Postsynaptic Potentials/physiology ; Female ; Gene Expression ; Humans ; Male ; Membrane Potentials/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Organ Culture Techniques ; tau Proteins/biosynthesis ; tau Proteins/genetics
Chemical Substances	Mapt protein, mouse ; tau Proteins
Language	English
Publishing date	2021-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2021.113766
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Article: Imbalances in the Hsp90 Chaperone Machinery: Implications for Tauopathies.

Shelton, Lindsey B / Koren, John / Blair, Laura J

Frontiers in neuroscience

2017 Volume 11, Page(s) 724

Abstract: The ATP-dependent 90 kDa heat shock protein, Hsp90, is a major regulator of protein triage, from assisting in nascent protein folding to refolding or degrading aberrant proteins. Tau, a microtubule associated protein, aberrantly accumulates in Alzheimer' ... ...

Abstract	The ATP-dependent 90 kDa heat shock protein, Hsp90, is a major regulator of protein triage, from assisting in nascent protein folding to refolding or degrading aberrant proteins. Tau, a microtubule associated protein, aberrantly accumulates in Alzheimer's disease (AD) and other neurodegenerative diseases, deemed tauopathies. Hsp90 binds to and regulates tau fate in coordination with a diverse group of co-chaperones. Imbalances in chaperone levels and activity, as found in the aging brain, can contribute to disease onset and progression. For example, the levels of the Hsp90 co-chaperone, FK506-binding protein 51 kDa (FKBP51), progressively increase with age.
Language	English
Publishing date	2017-12-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2017.00724
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Article ; Online: Fixed Time-Point Analysis Reveals Repetitive Mild Traumatic Brain Injury Effects on Resting State Functional Magnetic Resonance Imaging Connectivity and Neuro-Spatial Protein Profiles.

Sakthivel, Ravi / Criado-Marrero, Marangelie / Barroso, Daylin / Braga, Isadora M / Bolen, Mackenzie / Rubinovich, Uriel / Hery, Gabriela P / Grudny, Matteo M / Koren, John / Prokop, Stefan / Febo, Marcelo / Abisambra, Jose Francisco

Journal of neurotrauma

2023 Volume 40, Issue 19-20, Page(s) 2037–2049

Abstract: Repetitive mild traumatic brain injuries (rmTBIs) are serious trauma events responsible for the development of numerous neurodegenerative disorders. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the ... ...

Abstract	Repetitive mild traumatic brain injuries (rmTBIs) are serious trauma events responsible for the development of numerous neurodegenerative disorders. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps of the molecular mechanisms responsible for neurodegeneration. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. Using the Closed-Head Impact Model of Engineered Rotational Acceleration, or CHIMERA, we measured neural changes following injury, including brain volume, diffusion tensor imaging, and resting-state functional magnetic resonance imaging coupled with graph theory and functional connectivity analyses. We determined the effect of rmTBI on markers of gliosis and used NanoString-GeoMx to add a digital-spatial protein profiling analysis of neurodegenerative disease-associated proteins in gray and white matter regions. Our analyses revealed aberrant connectivity changes in the thalamus, independent of microstructural damage or neuroinflammation. We also identified distinct changes in the levels of proteins linked to various neurodegenerative processes including total and phospho-tau species and cell proliferation markers. Together, our data show that rmTBI significantly alters brain functional connectivity and causes distinct protein changes in morphologically intact brain areas.
MeSH term(s)	Humans ; Brain Concussion/complications ; Neurodegenerative Diseases/pathology ; Diffusion Tensor Imaging ; Brain/pathology ; Brain Injuries, Traumatic/complications ; Magnetic Resonance Imaging
Language	English
Publishing date	2023-04-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	645092-1
ISSN	1557-9042 ; 0897-7151
ISSN (online)	1557-9042
ISSN	0897-7151
DOI	10.1089/neu.2022.0464
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Article: Reconstructing the Hsp90/Tau Machine.

Jinwal, Umesh K / Koren, John / Dickey, Chad A

Current enzyme inhibition

2013 Volume 9, Issue 1, Page(s) 41–45

Abstract: Imbalanced protein load within cells is a critical aspect for most diseases of aging. In particular, the accumulation of proteins into neurotoxic aggregates is a common thread for a host of neurodegenerative diseases. Recent work demonstrates that age- ... ...

Abstract	Imbalanced protein load within cells is a critical aspect for most diseases of aging. In particular, the accumulation of proteins into neurotoxic aggregates is a common thread for a host of neurodegenerative diseases. Recent work demonstrates that age-related changes to the cellular chaperone repertoire contributes to abnormal buildup of the microtubule-associated protein tau that accumulates in a group of diseases termed tauopathies, the most common being Alzheimer's disease (AD). The Hsp90 co-chaperone repertoire has diverse effects on tau stability; some co-chaperones stabilize tau while others facilitate its clearance. We propose that each of these proteins may be novel therapeutic targets. While targeting Hsp90 directly may be deleterious at the organismal level, perhaps targeting individual co-chaperone activities will be more tolerable.
Language	English
Publishing date	2013-06-12
Publishing country	United Arab Emirates
Document type	Journal Article
ISSN	1573-4080
ISSN	1573-4080
DOI	10.2174/1573408011309010006
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Article ; Online: The Development of Hsp90β-Selective Inhibitors to Overcome Detriments Associated with

Mishra, Sanket J / Liu, Weiya / Beebe, Kristin / Banerjee, Monimoy / Kent, Caitlin N / Munthali, Vitumbiko / Koren, John / Taylor, John A / Neckers, Leonard M / Holzbeierlein, Jeffrey / Blagg, Brian S J

Journal of medicinal chemistry

2021 Volume 64, Issue 3, Page(s) 1545–1557

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 ...

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
MeSH term(s)	Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Silencing ; HSP90 Heat-Shock Proteins/antagonists & inhibitors ; HSP90 Heat-Shock Proteins/genetics ; Heterocyclic Compounds, 4 or More Rings/chemistry ; Heterocyclic Compounds, 4 or More Rings/pharmacology ; Humans ; Models, Molecular ; Molecular Conformation ; Neoplasms/drug therapy ; Protein Folding ; Small Molecule Libraries ; Structure-Activity Relationship ; Substrate Specificity ; Urinary Bladder Neoplasms/drug therapy
Chemical Substances	Antineoplastic Agents ; HSP90 Heat-Shock Proteins ; Heterocyclic Compounds, 4 or More Rings ; SNX 2112 ; Small Molecule Libraries
Language	English
Publishing date	2021-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c01700
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Article: Chaperone-dependent Neurodegeneration: A Molecular Perspective on Therapeutic Intervention.

Carman, Aaron / Kishinevsky, Sarah / Koren, John / Lou, Wenjie / Chiosis, Gabriela

Journal of Alzheimer's disease & Parkinsonism

2014 Volume 2013, Issue Suppl 10

Abstract: Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as "clients," have major roles in the pathogenesis of ... ...

Abstract	Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as "clients," have major roles in the pathogenesis of numerous neurological disorders, including tau in Alzheimer's disease, α-synuclein and LRRK2 in Parkinson's disease, SOD-1, TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as huntingtin in Huntington's disease. Recent work has demonstrated that the use of chemical compounds which inhibit the activity of molecular chaperones subsequently alter the fate of aberrant clients. Inhibition of Hsp90 and Hsc70, two major molecular chaperones, has led to a greater understanding of how chaperone triage decisions are made and how perturbing the chaperone system can promote clearance of these pathogenic clients. Described here are major pathways and components of several prominent neurological disorders. Also discussed is how treatment with chaperone inhibitors, predominately Hsp90 inhibitors which are selective for a diseased state, can relieve the burden of aberrant client signaling in these neurological disorders.
Language	English
Publishing date	2014-07-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2711981-6
ISSN	2161-0460
ISSN	2161-0460
DOI	10.4172/2161-0460.S10-007
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Article ; Online: Stressing Out Hsp90 in Neurotoxic Proteinopathies.

Inda, Carmen / Bolaender, Alexander / Wang, Tai / Gandu, Srinivasa R / Koren, John

Current topics in medicinal chemistry

2016 Volume 16, Issue 25, Page(s) 2829–2838

Abstract: A toxic accumulation of proteins is the hallmark pathology of several neurodegenerative disorders. Protein accumulation is regularly prevented by the network of molecular chaperone proteins, including and especially Hsp90. For reasons not yet elucidated, ...

Abstract	A toxic accumulation of proteins is the hallmark pathology of several neurodegenerative disorders. Protein accumulation is regularly prevented by the network of molecular chaperone proteins, including and especially Hsp90. For reasons not yet elucidated, Hsp90 and the molecular chaperones interact with, but do not degrade, these toxic proteins resulting in the pathogenic accumulation of proteins such as tau, in Alzheimer's Disease, and α-synuclein, in Parkinson's Disease. In this review, we describe the associations between Hsp90 and the pathogenic and driver proteins of several neurodegenerative disorders. We additionally describe how the inhibition of Hsp90 promotes the degradation of both mutant and pathogenic protein species in models of neurodegenerative diseases. We also examine the current state of Hsp90 inhibitors capable of crossing the blood-brain barrier; compounds which may be capable of slowing, preventing, and possible reversing neurodegenerative diseases.
MeSH term(s)	HSP90 Heat-Shock Proteins/metabolism ; Humans ; Neurodegenerative Diseases/metabolism ; tau Proteins/metabolism
Chemical Substances	HSP90 Heat-Shock Proteins ; tau Proteins
Language	English
Publishing date	2016-04-12
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/1568026616666160413141350
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Article ; Online: UQCRH downregulation promotes Warburg effect in renal cell carcinoma cells.

Luo, Yanting / Medina Bengtsson, Louise / Wang, Xuechun / Huang, Tianhe / Liu, Guoqiang / Murphy, Sean / Wang, Caiqin / Koren, John / Schafer, Zachary / Lu, Xin

Scientific reports

2020 Volume 10, Issue 1, Page(s) 15021

Abstract: Ubiquinol-cytochrome c reductase hinge protein (UQCRH) is the hinge protein for the multi-subunit complex III of the mitochondrial electron transport chain and is involved in the electron transfer reaction between cytochrome c1 and c. Recent genome-wide ... ...

Abstract	Ubiquinol-cytochrome c reductase hinge protein (UQCRH) is the hinge protein for the multi-subunit complex III of the mitochondrial electron transport chain and is involved in the electron transfer reaction between cytochrome c1 and c. Recent genome-wide transcriptomic and epigenomic profiling of clear cell renal cell carcinoma (ccRCC) by The Cancer Genome Atlas (TCGA) identified UQCRH as the top-ranked gene showing inverse correlation between DNA hypermethylation and mRNA downregulation. The function and underlying mechanism of UQCRH in the Warburg effect metabolism of ccRCC have not been characterized. Here, we verified the clinical association of low UQCRH expression and shorter survival of ccRCC patients through in silico analysis and identified KMRC2 as a highly relevant ccRCC cell line that displays hypermethylation-induced UQCRH extinction. Ectopic overexpression of UQCRH in KMRC2 restored mitochondrial membrane potential, increased oxygen consumption, and attenuated the Warburg effect at the cellular level. UQCRH overexpression in KMRC2 induced higher apoptosis and slowed down in vitro and in vivo tumor growth. UQCRH knockout by CRISPR/Cas9 had little impact on the metabolism and proliferation of 786O ccRCC cell line, suggesting the dispensable role of UQCRH in cells that have entered a Warburg-like state through other mechanisms. Together, our study suggests that loss of UQCRH expression by hypermethylation may promote kidney carcinogenesis through exacerbating the functional decline of mitochondria thus reinforcing the Warburg effect.
MeSH term(s)	Animals ; Apoptosis ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology ; Cell Line, Tumor ; DNA Methylation ; Down-Regulation ; Electron Transport Complex III/genetics ; Electron Transport Complex III/metabolism ; Humans ; Kidney Neoplasms/genetics ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/pathology ; Male ; Mice ; Warburg Effect, Oncologic
Chemical Substances	UQCRH protein, human ; Electron Transport Complex III (EC 7.1.1.8)
Language	English
Publishing date	2020-09-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-72107-2
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Article ; Online: The earliest tau dysfunction in Alzheimer's disease? Tau phosphorylated at s422 as a toxic seed.

Voss, Kellen / Koren, John / Dickey, Chad A

The American journal of pathology

2011 Volume 179, Issue 5, Page(s) 2148–2151

MeSH term(s)	Alzheimer Disease/pathology ; Cholinergic Neurons/pathology ; Cognitive Dysfunction/pathology ; Female ; Humans ; Male ; Prosencephalon/pathology
Language	English
Publishing date	2011-09-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2011.08.020
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