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The small molecule KHS101 induces bioenergetic dysfunction in glioblastoma cells through inhibition of mitochondrial HSPD1

Euan S. Polson, Verena B. Kuchler, View ORCID ProfileChristopher Abbosh, View ORCID ProfileEdith M. Ross, View ORCID ProfileRyan K. Mathew, View ORCID ProfileHester A. Beard, Eulashini Chuntharpursat-Bon, Jennifer Williams, Bárbara Da Silva, Hao Shao, Anjana Patel, Adam J. Davies, View ORCID ProfileAlastair Droop, Hollie B.S. Griffiths, View ORCID ProfilePaul Chumas, View ORCID ProfileSusan C. Short, View ORCID ProfileMihaela Lorger, Jason Gestwicki, View ORCID ProfileLee D. Roberts, View ORCID ProfileRobin S. Bon, View ORCID ProfileSimon J. Allison, Shoutian Zhu, View ORCID ProfileFlorian Markowetz, View ORCID ProfileHeiko Wurdak
doi: https://doi.org/10.1101/205203
Euan S. Polson
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Verena B. Kuchler
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Christopher Abbosh
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Edith M. Ross
2Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK.
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Ryan K. Mathew
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
3Department of Neurosurgery, Leeds General Infirmary, Leeds, LS1 3EX, UK.
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Hester A. Beard
4School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
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Eulashini Chuntharpursat-Bon
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Jennifer Williams
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Bárbara Da Silva
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Hao Shao
5Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, 675 Nelson Rising Ln., San Francisco, California 94158, USA.
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Anjana Patel
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Adam J. Davies
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Alastair Droop
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Hollie B.S. Griffiths
6School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK.
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Paul Chumas
3Department of Neurosurgery, Leeds General Infirmary, Leeds, LS1 3EX, UK.
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Susan C. Short
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Mihaela Lorger
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Jason Gestwicki
5Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, 675 Nelson Rising Ln., San Francisco, California 94158, USA.
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Lee D. Roberts
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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Robin S. Bon
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
4School of Chemistry, University of Leeds, Leeds, LS2 9JT, UK.
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Simon J. Allison
6School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK.
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Shoutian Zhu
7California Institute for Biomedical Research, 11119 North Torrey Pines Road, Suite 100, La Jolla, CA 92037, USA.
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Florian Markowetz
2Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK.
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Heiko Wurdak
1School of Medicine, University of Leeds, Leeds, LS2 9JT, UK.
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  • ORCID record for Heiko Wurdak
  • For correspondence: h.wurdak@leeds.ac.uk
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Abstract

Pharmacological inhibition of uncontrolled cell growth with small molecule inhibitors is a potential strategy against glioblastoma multiforme (GBM), the most malignant primary brain cancer. Phenotypic profiling of the neurogenic small molecule KHS101 revealed the chemical induction of lethal cellular degradation in molecularly-diverse GBM cells, independent of their tumor subtype, whereas non-cancerous brain cells remained viable. Mechanism-of-action (MOA) studies showed that KHS101 specifically bound and inhibited the mitochondrial chaperone HSPD1. In GBM but not non-cancerous brain cells, KHS101 elicited the aggregation of an enzymatic network that regulates energy metabolism. Compromised glycolysis and oxidative phosphorylation (OXPHOS) resulted in the metabolic energy depletion in KHS101-treated GBM cells. Consistently, KHS101 induced key mitochondrial unfolded protein response factor DDIT3 in vitro and in vivo, and significantly reduced intracranial GBM xenograft tumor growth upon systemic administration, without discernible side effects. These findings suggest targeting of HSPD1-dependent oncometabolic pathways as an anti-GBM therapy.

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Posted October 18, 2017.
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The small molecule KHS101 induces bioenergetic dysfunction in glioblastoma cells through inhibition of mitochondrial HSPD1
Euan S. Polson, Verena B. Kuchler, Christopher Abbosh, Edith M. Ross, Ryan K. Mathew, Hester A. Beard, Eulashini Chuntharpursat-Bon, Jennifer Williams, Bárbara Da Silva, Hao Shao, Anjana Patel, Adam J. Davies, Alastair Droop, Hollie B.S. Griffiths, Paul Chumas, Susan C. Short, Mihaela Lorger, Jason Gestwicki, Lee D. Roberts, Robin S. Bon, Simon J. Allison, Shoutian Zhu, Florian Markowetz, Heiko Wurdak
bioRxiv 205203; doi: https://doi.org/10.1101/205203
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The small molecule KHS101 induces bioenergetic dysfunction in glioblastoma cells through inhibition of mitochondrial HSPD1
Euan S. Polson, Verena B. Kuchler, Christopher Abbosh, Edith M. Ross, Ryan K. Mathew, Hester A. Beard, Eulashini Chuntharpursat-Bon, Jennifer Williams, Bárbara Da Silva, Hao Shao, Anjana Patel, Adam J. Davies, Alastair Droop, Hollie B.S. Griffiths, Paul Chumas, Susan C. Short, Mihaela Lorger, Jason Gestwicki, Lee D. Roberts, Robin S. Bon, Simon J. Allison, Shoutian Zhu, Florian Markowetz, Heiko Wurdak
bioRxiv 205203; doi: https://doi.org/10.1101/205203

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