Timothy Haystead

Overview:

Haystead, Timothy. Using chemical biology approaches to define novel drug targets for the treatment of hypertension, obesity, cancer, inflammatory and infectious disease. 

                                                                                                                                 

Research Interests

The major focus of my laboratory is the discovery and development of novel small molecule inhibitors targeting purine-utilizing proteins involved in various aspects of human disease. Specific targets of interest include heat shock protein 90 (Hsp90), heat shock protein 70 (Hsp70), fatty acid synthase, acetyl CoA Carboxylase, DAPK3 (ZIPK), PIM kinases, dengue fever non-structural protein 5 (NS5) and TAK1 (haysteadlab.com). Hsp90, Hsp70 and fatty acid synthase all have cancer and antiviral therapeutic indications and we are actively developing a series molecules specifically targeting these proteins that were scratch discovered in our laboratory. We have also developed a series of novel imaging molecules based on our Hsp90 inhibitor series that have utility as both diagnostics and potentially curative strategies for a number human cancers and viral infections. Our DAPK(ZIPK) and PIMK inhibitors have shown indications as anti-hypertensive agents as well as having utility in preventing reperfusion injury after stroke. Our TAK1 inhibitor program (discovered with the Derbyshire Laboratory, Department of Chemistry, Duke) has defined a highly potent and selective inhibitor of TAK1 kinase an important protein kinases thought to mediate the actions of proinflammatory cytokines such as TNFa, IL1 and TGFb. The foundations of these programs are based on the development a chemoproteomic strategy utilizing affinity methods combined with in house organic synthetic chemistry.

Positions:

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1988

University of Dundee (United Kingdom)

Grants:

Pseudomonas Invasion and the Role of Caveolin-2

Administered By
Medicine, Pulmonary, Allergy, and Critical Care Medicine
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

Proteomic/Genetic Approaches to Monoamine Transporters

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Co-Mentor
Start Date
End Date

The Duke Multidisciplinary Training Program in Pediatric Lung Disease

Administered By
Pediatrics, Pulmonary and Sleep Medicine
Awarded By
National Institutes of Health
Role
Faculty Member
Start Date
End Date

Improving the Oral Bioavailability and in vivo efficacy of the TAK 1 inhibitor, Takinib.

Administered By
Pharmacology & Cancer Biology
Awarded By
North Carolina Biotechnology Center
Role
Principal Investigator
Start Date
End Date

Co-crystalization of inducible Heat shock Protein 70 with the inhibitor HS-72 and structural analogs.

Administered By
Pharmacology & Cancer Biology
Awarded By
Open Philanthropy Project
Role
Principal Investigator
Start Date
End Date

Publications:

The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.

Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.
Authors
Woodford, MR; Baker-Williams, AJ; Sager, RA; Backe, SJ; Blanden, AR; Hashmi, F; Kancherla, P; Gori, A; Loiselle, DR; Castelli, M; Serapian, SA; Colombo, G; Haystead, TA; Jensen, SM; Stetler-Stevenson, WG; Loh, SN; Schmidt, LS; Linehan, WM; Bah, A; Bourboulia, D; Bratslavsky, G; Mollapour, M
MLA Citation
Woodford, Mark R., et al. “The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.Nat Struct Mol Biol, vol. 28, no. 8, Aug. 2021, pp. 662–70. Pubmed, doi:10.1038/s41594-021-00633-2.
URI
https://scholars.duke.edu/individual/pub1494606
PMID
34381247
Source
pubmed
Published In
Nat Struct Mol Biol
Volume
28
Published Date
Start Page
662
End Page
670
DOI
10.1038/s41594-021-00633-2

Understanding the sources of errors in ex vivo Hsp90 molecular imaging for rapid-on-site breast cancer diagnosis.

Overexpression of heat shock protein 90 (Hsp90) on the surface of breast cancer cells makes it an attractive molecular biomarker for breast cancer diagnosis. Before a ubiquitous diagnostic method can be established, an understanding of the systematic errors in Hsp90-based imaging is essential. In this study, we investigated three factors that may influence the sensitivity of ex vivo Hsp90 molecular imaging: time-dependent tissue viability, nonspecific diffusion of an Hsp90 specific probe (HS-27), and contact-based imaging. These three factors will be important considerations when designing any diagnostic imaging strategy based on fluorescence imaging of a molecular target on tissue samples.
Authors
Wang, R; Alvarez, DA; Crouch, BT; Pilani, A; Lam, C; Zhu, C; Hughes, P; Katz, D; Haystead, T; Ramanujam, N
MLA Citation
Wang, Roujia, et al. “Understanding the sources of errors in ex vivo Hsp90 molecular imaging for rapid-on-site breast cancer diagnosis.Biomed Opt Express, vol. 12, no. 4, Apr. 2021, pp. 2299–311. Pubmed, doi:10.1364/BOE.418818.
URI
https://scholars.duke.edu/individual/pub1476406
PMID
33996230
Source
pubmed
Published In
Biomedical Optics Express
Volume
12
Published Date
Start Page
2299
End Page
2311
DOI
10.1364/BOE.418818

Transcription factor-driven alternative localization of Cryptococcus neoformans superoxide dismutase.

Cryptococcus neoformans is an opportunistic fungal pathogen whose pathogenic lifestyle is linked to its ability to cope with fluctuating levels of copper (Cu), an essential metal involved in multiple virulence mechanisms, within distinct host niches. During lethal cryptococcal meningitis in the brain, C. neoformans senses a Cu-deficient environment and is highly dependent on its ability to scavenge trace levels of Cu from its host and adapt to Cu scarcity to successfully colonize this niche. In this study, we demonstrate for this critical adaptation, the Cu-sensing transcription factor Cuf1 differentially regulates the expression of the SOD1 and SOD2 superoxide dismutases in novel ways. Genetic and transcriptional analysis reveals Cuf1 specifies 5'-truncations of the SOD1 and SOD2 mRNAs through specific binding to Cu responsive elements within their respective promoter regions. This results in Cuf1-dependent repression of the highly abundant SOD1 and simultaneously induces expression of two isoforms of SOD2, the canonical mitochondrial targeted isoform and a novel alternative cytosolic isoform, from a single alternative transcript produced specifically under Cu limitation. The generation of cytosolic Sod2 during Cu limitation is required to maintain cellular antioxidant defense against superoxide stress both in vitro and in vivo. Further, decoupling Cuf1 regulation of Sod2 localization compromises the ability of C. neoformans to colonize organs in murine models of cryptococcosis. Our results provide a link between transcription factor-mediated alteration of protein localization and cell proliferation under stress, which could impact tissue colonization by a fungal pathogen.
Authors
Smith, AD; Garcia-Santamarina, S; Ralle, M; Loiselle, DR; Haystead, TA; Thiele, DJ
MLA Citation
Smith, Aaron D., et al. “Transcription factor-driven alternative localization of Cryptococcus neoformans superoxide dismutase.The Journal of Biological Chemistry, vol. 296, Jan. 2021, p. 100391. Epmc, doi:10.1016/j.jbc.2021.100391.
URI
https://scholars.duke.edu/individual/pub1473902
PMID
33567338
Source
epmc
Published In
The Journal of Biological Chemistry
Volume
296
Published Date
Start Page
100391
DOI
10.1016/j.jbc.2021.100391

Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1.

Heat shock factor 1 (HSF1) is a cellular stress-protective transcription factor exploited by a wide range of cancers to drive proliferation, survival, invasion, and metastasis. Nuclear HSF1 abundance is a prognostic indicator for cancer severity, therapy resistance, and shortened patient survival. The HSF1 gene was amplified, and nuclear HSF1 abundance was markedly increased in prostate cancers and particularly in neuroendocrine prostate cancer (NEPC), for which there are no available treatment options. Despite genetic validation of HSF1 as a therapeutic target in a range of cancers, a direct and selective small-molecule HSF1 inhibitor has not been validated or developed for use in the clinic. We described the identification of a direct HSF1 inhibitor, Direct Targeted HSF1 InhiBitor (DTHIB), which physically engages HSF1 and selectively stimulates degradation of nuclear HSF1. DTHIB robustly inhibited the HSF1 cancer gene signature and prostate cancer cell proliferation. In addition, it potently attenuated tumor progression in four therapy-resistant prostate cancer animal models, including an NEPC model, where it caused profound tumor regression. This study reports the identification and validation of a direct HSF1 inhibitor and provides a path for the development of a small-molecule HSF1-targeted therapy for prostate cancers and other therapy-resistant cancers.
Authors
Dong, B; Jaeger, AM; Hughes, PF; Loiselle, DR; Hauck, JS; Fu, Y; Haystead, TA; Huang, J; Thiele, DJ
MLA Citation
Dong, Bushu, et al. “Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1.Sci Transl Med, vol. 12, no. 574, Dec. 2020. Pubmed, doi:10.1126/scitranslmed.abb5647.
URI
https://scholars.duke.edu/individual/pub1469926
PMID
33328331
Source
pubmed
Published In
Sci Transl Med
Volume
12
Published Date
DOI
10.1126/scitranslmed.abb5647

TAK1: a potent tumour necrosis factor inhibitor for the treatment of inflammatory diseases.

Aberrant tumour necrosis factor (TNF) signalling is a hallmark of many inflammatory diseases including rheumatoid arthritis (RA), irritable bowel disease and lupus. Maladaptive TNF signalling can lead to hyper active downstream nuclear factor (NF)-κβ signalling in turn amplifying a cell's inflammatory response and exacerbating disease. Within the TNF intracellular inflammatory signalling cascade, transforming growth factor-β-activated kinase 1 (TAK1) has been shown to play a critical role in mediating signal transduction and downstream NF-κβ activation. Owing to its role in TNF inflammatory signalling, TAK1 has become a potential therapeutic target for the treatment of inflammatory diseases such as RA. This review highlights the current development of targeting the TNF-TAK1 signalling axis as a novel therapeutic strategy for the treatment of inflammatory diseases.
Authors
Totzke, J; Scarneo, SA; Yang, KW; Haystead, TAJ
MLA Citation
Totzke, Juliane, et al. “TAK1: a potent tumour necrosis factor inhibitor for the treatment of inflammatory diseases.Open Biol, vol. 10, no. 9, Sept. 2020, p. 200099. Pubmed, doi:10.1098/rsob.200099.
URI
https://scholars.duke.edu/individual/pub1460011
PMID
32873150
Source
pubmed
Published In
Open Biology
Volume
10
Published Date
Start Page
200099
DOI
10.1098/rsob.200099