University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Jason E. Gestwicki, PhD

Jason E. Gestwicki, PhD

Associate Professor, Pharmaceutical Chemistry, UCSF

Cancer Center Program Memberships

Experimental Therapeutics

Research Summary

The Gestwicki Laboratory is interested in molecular chaperones, protein homeostasis and protein misfolding disorders. To approach the big questions in this area, we use a chemical biology strategy that includes the discovery and optimization of new chemical inhibitors. We use these chemical probes to acutely perturb chaperone functions, revealing how these systems normally protect from cancer and neurodegeneration. Many of our chemical probes target allosteric and protein-protein interaction sites on the molecular chaperones and we have a significant interest in discovering inhibitors of "difficult" targets. We hope to better understand the logic of protein folding and misfolding and use this information to design more effective therapies.

Education

State University of New York - Fredonia, B.S., 1997, Chemistry
University of Wisconsin – Madison (with Laura L. Kiessling), PhD, 2002, Biochemistry
Stanford University (with Gerald R. Crabtree), 2005, Post-doctoral, Chemical Biology


Professional Experience

  • 2013 – present
    University of California at San Francisco Associate Professor in Residence, Department of Pharmaceutical Chemistry Associate Professor, Institute for Neurodegenerative Diseases
  • 2011 - 2013
    University of Michigan Associate Professor, Departments of Pathology and Biological Chemistry William B. Pratt Collegiate Professor, Life Sciences Institute Director, Center for Chemical Genomics (CCG)
  • 2005 – 2011
    University of Michigan Assistant Professor, Departments of Pathology and Biological Chemistry Research Assistant Professor, Life Sciences Institute

Honors & Awards

  • 2015
    UCSF School of Pharmacy, Excellence in Teaching
  • 2014
    Named “Young Innovator” at UCSF
  • 2012
    Elected Fellow, American Association for the Advancement of Science (AAAS)
  • 2009
    National Science Foundation CAREER award
  • 2006
    McKnight Foundation Brain Disorders Award (with Andrew Lieberman and William Pratt)
  • 2005
    Biological Sciences Scholar (University of Michigan)
  • 2001
    Sigrid Liermo Award (Departmental Service; UW Madison)
  • 1998
    National Institutes of Health Biotechnology Training Program Fellowship

Selected Publications

  1. Rinaldi S, Assimon VA, Young ZT, Morra G, Shao H, Taylor IR, Gestwicki JE, Colombo G. A Local Allosteric Network in Heat Shock Protein 70 (Hsp70) Links Inhibitor Binding to Enzyme Activity and Distal Protein-Protein Interactions. ACS Chem Biol. 2018 Nov 08.
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  2. Freilich R, Betegon M, Tse E, Mok SA, Julien O, Agard DA, Southworth DR, Takeuchi K, Gestwicki JE. Competing protein-protein interactions regulate binding of Hsp27 to its client protein tau. Nat Commun. 2018 Nov 01; 9(1):4563.
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  3. Gestwicki JE, Shao H. Inhibitors and chemical probes for molecular chaperone networks. J Biol Chem. 2018 Sep 13.
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  4. Lee E, Ouzounova M, Piranlioglu R, Ma MT, Guzel M, Marasco D, Chadli A, Gestwicki JE, Cowell JK, Wicha MS, Hassan KA, Korkaya H. The pleiotropic effects of TNFa in breast cancer subtypes is regulated by TNFAIP3/A20. Oncogene. 2018 Aug 30.
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  5. Polson ES, Kuchler VB, Abbosh C, Ross EM, Mathew RK, Beard HA, da Silva B, Holding AN, Ballereau S, Chuntharpursat-Bon E, Williams J, Griffiths HBS, Shao H, Patel A, Davies AJ, Droop A, Chumas P, Short SC, Lorger M, Gestwicki JE, Roberts LD, Bon RS, Allison SJ, Zhu S, Markowetz F, Wurdak H. KHS101 disrupts energy metabolism in human glioblastoma cells and reduces tumor growth in mice. Sci Transl Med. 2018 Aug 15; 10(454).
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  6. Shao H, Li X, Moses MA, Gilbert LA, Kalyanaraman C, Young ZT, Chernova M, Journey SN, Weissman JS, Hann B, Jacobson MP, Neckers LM, Gestwicki JE. Exploration of Benzothiazole-Rhodacyanines as Allosteric Inhibitors of Protein-Protein Interactions with Heat Shock Protein 70 (Hsp70). J Med Chem. 2018 Jun 28.
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  7. Opoku-Nsiah KA, Gestwicki JE. Aim for the core: suitability of the ubiquitin-independent 20S proteasome as a drug target in neurodegeneration. Transl Res. 2018 Aug; 198:48-57.
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  8. Ran X, Gestwicki JE. Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area. Curr Opin Chem Biol. 2018 Jun 13; 44:75-86.
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  9. Glazier AA, Hafeez N, Mellacheruvu D, Basrur V, Nesvizhskii AI, Lee LM, Shao H, Tang V, Yob JM, Gestwicki JE, Helms AS, Day SM. HSC70 is a chaperone for wild-type and mutant cardiac myosin binding protein C. JCI Insight. 2018 Jun 07; 3(11).
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  10. Schwarz DMC, Gestwicki JE. Revisiting the "Art of the Chemical Probe". ACS Chem Biol. 2018 May 18; 13(5):1109-1110.
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  11. Moses MA, Kim YS, Rivera-Marquez GM, Oshima N, Watson MJ, Beebe K, Wells C, Lee S, Zuehlke AD, Shao H, Bingman WE, Kumar V, Malhotra S, Weigel NL, Gestwicki JE, Trepel J, Neckers LM. Targeting the Hsp40/Hsp70 chaperone axis as a novel strategy to treat castration-resistant prostate cancer. Cancer Res. 2018 May 15.
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  12. Taylor IR, Ahmad A, Wu T, Nordhues BA, Bhullar A, Gestwicki JE, Zuiderweg ERP. The disorderly conduct of Hsc70 and its interaction with the Alzheimer's related Tau protein. J Biol Chem. 2018 May 15.
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  13. Mok SA, Condello C, Freilich R, Gillies A, Arhar T, Oroz J, Kadavath H, Julien O, Assimon VA, Rauch JN, Dunyak BM, Lee J, Tsai FTF, Wilson MR, Zweckstetter M, Dickey CA, Gestwicki JE. Mapping interactions with the chaperone network reveals factors that protect against tau aggregation. Nat Struct Mol Biol. 2018 May; 25(5):384-393.
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  14. Ran X, Burchfiel ET, Dong B, Rettko NJ, Dunyak BM, Shao H, Thiele DJ, Gestwicki JE. Rational design and screening of peptide-based inhibitors of heat shock factor 1 (HSF1). Bioorg Med Chem. 2018 Apr 07.
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  15. Freilich R, Arhar T, Abrams JL, Gestwicki JE. Protein-Protein Interactions in the Molecular Chaperone Network. Acc Chem Res. 2018 Apr 03.
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  16. Ouimet CM, Dawod M, Grinias J, Assimon VA, Lodge J, Mapp AK, Gestwicki JE, Kennedy RT. Protein cross-linking capillary electrophoresis at increased throughput for a range of protein-protein interactions. Analyst. 2018 Mar 22.
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  17. Min SW, Sohn PD, Li Y, Devidze N, Johnson JR, Krogan NJ, Masliah E, Mok SA, Gestwicki JE, Gan L. SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy. J Neurosci. 2018 Apr 11; 38(15):3680-3688.
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  18. Taylor IR, Dunyak BM, Komiyama T, Shao H, Ran X, Assimon VA, Kalyanaraman C, Rauch JN, Jacobson MP, Zuiderweg ERP, Gestwicki JE. High Throughput Screen for Inhibitors of Protein-Protein Interactions in a Reconstituted Heat Shock Protein 70 (Hsp70) Complex. J Biol Chem. 2018 Feb 02.
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  19. Young ZT, Mok SA, Gestwicki JE. Therapeutic Strategies for Restoring Tau Homeostasis. Cold Spring Harb Perspect Med. 2018 Jan 02; 8(1).
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  20. Cesa LC, Shao H, Srinivasan SR, Tse E, Jain C, Zuiderweg ERP, Southworth DR, Mapp AK, Gestwicki JE. X-linked inhibitor of apoptosis protein (XIAP) is a client of heat shock protein 70 (Hsp70) and a biomarker of its inhibition. J Biol Chem. 2018 Feb 16; 293(7):2370-2380.
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