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. Jackson JW, Rivera-Marquez G, Beebe K, Tran AD, Trepel JB, Gestwicki JE, Blagg BSJ, Ohkubo S, Neckers LM. Pharmacologic dissection of the overlapping impact of heat shock protein family members on platelet function. J Thromb Haemost. 2020 Feb 05.
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  2. Singh JK, Hutt DM, Tait B, Guy NC, Sivils JC, Ortiz NR, Payan AN, Komaragiri SK, Owens JJ, Culbertson D, Blair LJ, Dickey C, Kuo SY, Finley D, Dyson HJ, Cox MB, Chaudhary J, Gestwicki JE, Balch WE. Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone. Cell Chem Biol. 2020 Feb 03.
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  3. Shao H, Gestwicki JE. Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor, JG-98. Bioorg Med Chem Lett. 2020 Jan 11; 126954.
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  4. Chen X, Li Y, Wang C, Tang Y, Mok SA, Tsai RM, Rojas JC, Karydas A, Miller BL, Boxer AL, Gestwicki JE, Arkin M, Cuervo AM, Gan L. Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy. Mol Neurodegener. 2020 Jan 06; 15(1):2.
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  5. Ravalin M, Basu K, Gestwicki JE, Craik CS. End-Binding E3 Ubiquitin Ligases Enable Protease Signaling. ACS Chem Biol. 2019 Nov 20.
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  6. Eftekharzadeh B, Banduseela VC, Chiesa G, Martínez-Cristóbal P, Rauch JN, Nath SR, Schwarz DMC, Shao H, Marin-Argany M, Di Sanza C, Giorgetti E, Yu Z, Pierattelli R, Felli IC, Brun-Heath I, García J, Nebreda ÁR, Gestwicki JE, Lieberman AP, Salvatella X. Author Correction: Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor. Nat Commun. 2019 Oct 07; 10(1):4605.
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  7. Chen JJ, Nathaniel DL, Raghavan P, Nelson M, Tian R, Tse E, Hong JY, See SK, Mok SA, Hein MY, Southworth DR, Grinberg LT, Gestwicki JE, Leonetti MD, Kampmann M. Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation. J Biol Chem. 2019 Dec 13; 294(50):18952-18966.
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  8. Sohn PD, Huang CT, Yan R, Fan L, Tracy TE, Camargo CM, Montgomery KM, Arhar T, Mok SA, Freilich R, Baik J, He M, Gong S, Roberson ED, Karch CM, Gestwicki JE, Xu K, Kosik KS, Gan L. Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis. Neuron. 2019 Nov 06; 104(3):458-470.e5.
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  9. Wang C, Scott SM, Sun S, Zhao P, Hutt DM, Shao H, Gestwicki JE, Balch WE. Individualized Management of Genetic Diversity in Niemann-Pick C1 through Modulation of the Hsp70 Chaperone System. Hum Mol Genet. 2019 Sep 11.
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  10. Eftekharzadeh B, Banduseela VC, Chiesa G, Martínez-Cristóbal P, Rauch JN, Nath SR, Schwarz DMC, Shao H, Marin-Argany M, Di Sanza C, Giorgetti E, Yu Z, Pierattelli R, Felli IC, Brun-Heath I, García J, Nebreda ÁR, Gestwicki JE, Lieberman AP, Salvatella X. Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor. Nat Commun. 2019 08 08; 10(1):3562.
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  11. Molnar KS, Dunyak BM, Su B, Izrayelit Y, McGlasson-Naumann B, Hamilton PD, Qian M, Covey DF, Gestwicki JE, Makley LN, Andley UP. Mechanism of Action of VP1-001 in cryAB(R120G)-Associated and Age-Related Cataracts. Invest Ophthalmol Vis Sci. 2019 08 01; 60(10):3320-3331.
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  12. Ravalin M, Theofilas P, Basu K, Opoku-Nsiah KA, Assimon VA, Medina-Cleghorn D, Chen YF, Bohn MF, Arkin M, Grinberg LT, Craik CS, Gestwicki JE. Specificity for latent C termini links the E3 ubiquitin ligase CHIP to caspases. Nat Chem Biol. 2019 08; 15(8):786-794.
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  13. Lee E, Ouzounova M, Piranlioglu R, Ma MT, Guzel M, Marasco D, Chadli A, Gestwicki JE, Cowell JK, Wicha MS, Hassan KA, Korkaya H. Correction: The pleiotropic effects of TNFa in breast cancer subtypes is regulated by TNFAIP3/A20. Oncogene. 2019 Jul; 38(28):5749.
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  14. Moss SM, Taylor IR, Ruggero D, Gestwicki JE, Shokat KM, Mukherjee S. A Legionella pneumophila Kinase Phosphorylates the Hsp70 Chaperone Family to Inhibit Eukaryotic Protein Synthesis. Cell Host Microbe. 2019 03 13; 25(3):454-462.e6.
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  15. Taguwa S, Yeh MT, Rainbolt TK, Nayak A, Shao H, Gestwicki JE, Andino R, Frydman J. Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease. Cell Rep. 2019 01 22; 26(4):906-920.e3.
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  16. Zaiter SS, Huo Y, Tiew FY, Gestwicki JE, McAlpine SR. Designing de Novo Small Molecules That Control Heat Shock Protein 70 (Hsp70) and Heat Shock Organizing Protein (HOP) within the Chaperone Protein-Folding Machinery. J Med Chem. 2019 01 24; 62(2):742-761.
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  17. Meister-Broekema M, Freilich R, Jagadeesan C, Rauch JN, Bengoechea R, Motley WW, Kuiper EFE, Minoia M, Furtado GV, van Waarde MAWH, Bird SJ, Rebelo A, Zuchner S, Pytel P, Scherer SS, Morelli FF, Carra S, Weihl CC, Bergink S, Gestwicki JE, Kampinga HH. Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks. Nat Commun. 2018 12 17; 9(1):5342.
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  18. Pabon NA, Xia Y, Estabrooks SK, Ye Z, Herbrand AK, Süß E, Biondi RM, Assimon VA, Gestwicki JE, Brodsky JL, Camacho CJ, Bar-Joseph Z. Predicting protein targets for drug-like compounds using transcriptomics. PLoS Comput Biol. 2018 12; 14(12):e1006651.
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  19. Kampinga HH, Andreasson C, Barducci A, Cheetham ME, Cyr D, Emanuelsson C, Genevaux P, Gestwicki JE, Goloubinoff P, Huerta-Cepas J, Kirstein J, Liberek K, Mayer MP, Nagata K, Nillegoda NB, Pulido P, Ramos C, De Los Rios P, Rospert S, Rosenzweig R, Sahi C, Taipale M, Tomiczek B, Ushioda R, Young JC, Zimmermann R, Zylicz A, Zylicz M, Craig EA, Marszalek J. Function, evolution, and structure of J-domain proteins. Cell Stress Chaperones. 2019 01; 24(1):7-15.
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  20. 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 11 16; 13(11):3142-3152.
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