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
Cell Biology
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:

Heat shock protein 90-targeted photodynamic therapy enables treatment of subcutaneous and visceral tumors.

Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a tumor-localizing strategy for PDT, exploiting the high expression of heat shock protein 90 (Hsp90) in cancer cells to retain high concentrations of PS by tethering a small molecule Hsp90 inhibitor to a PS (verteporfin, VP) to create an Hsp90-targeted PS (HS201). HS201 accumulates to a greater extent than VP in breast cancer cells both in vitro and in vivo, resulting in increased treatment efficacy of HS201-PDT in various human breast cancer xenografts regardless of molecular and clinical subtypes. The therapeutic index achieved with Hsp90-targeted PDT would permit treatment not only of localized tumors, but also more diffusely infiltrating processes such as inflammatory breast cancer.
Authors
Kaneko, K; Osada, T; Morse, MA; Gwin, WR; Ginzel, JD; Snyder, JC; Yang, X-Y; Liu, C-X; Diniz, MA; Bodoor, K; Hughes, PF; Haystead, TA; Lyerly, HK
MLA Citation
Kaneko, Kensuke, et al. “Heat shock protein 90-targeted photodynamic therapy enables treatment of subcutaneous and visceral tumors.Commun Biol, vol. 3, no. 1, May 2020, p. 226. Pubmed, doi:10.1038/s42003-020-0956-7.
URI
https://scholars.duke.edu/individual/pub1441154
PMID
32385408
Source
pubmed
Published In
Communications Biology
Volume
3
Published Date
Start Page
226
DOI
10.1038/s42003-020-0956-7

Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice.

OBJECTIVES: To examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells. METHODS: Following the induction of CIA, mice were treated daily with takinib (50 mg/kg) and clinical scores assessed. Thirty-six days post-CIA induction, histology was performed on various joints of treated and vehicle-treated animals. Inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation were quantified. Furthermore, pharmacokinetics of takinib were evaluated by LC-MS in various tissues. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells were cultured with 10 μM takinib and cytokine secretion analyzed by cytokine/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48 h cultures in the presence or absence of tumor necrosis factor (TNF). RESULTS: Here, we show takinib's ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p < 0.001). TAK1 inhibition reduced inflammation (p < 0.01), cartilage damage (p < 0.01), pannus, bone resorption, and periosteal bone formation and periosteal bone width in all joints of treated mice compared to vehicle treated. Significant reduction of inflammation (p < 0.004) and cartilage damage (p < 0.004) were observed in the knees of diseased treated animals, with moderate reduction seen in the forepaws and hind paws. Furthermore, the pharmacokinetics of takinib show rapid plasma clearance (t½ = 21 min). In stimulated RA-FLS cells, takinib reduced GROα, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling. CONCLUSION: Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.
Authors
Scarneo, SA; Eibschutz, LS; Bendele, PJ; Yang, KW; Totzke, J; Hughes, P; Fox, DA; Haystead, TAJ
MLA Citation
Scarneo, Scott A., et al. “Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice.Arthritis Res Ther, vol. 21, no. 1, Dec. 2019, p. 292. Pubmed, doi:10.1186/s13075-019-2073-x.
URI
https://scholars.duke.edu/individual/pub1424782
PMID
31847895
Source
pubmed
Published In
Arthritis Research & Therapy
Volume
21
Published Date
Start Page
292
DOI
10.1186/s13075-019-2073-x

Targeting Pim Kinases and DAPK3 to Control Hypertension.

Sustained vascular smooth muscle hypercontractility promotes hypertension and cardiovascular disease. The etiology of hypercontractility is not completely understood. New therapeutic targets remain vitally important for drug discovery. Here we report that Pim kinases, in combination with DAPK3, regulate contractility and control hypertension. Using a co-crystal structure of lead molecule (HS38) in complex with DAPK3, a dual Pim/DAPK3 inhibitor (HS56) and selective DAPK3 inhibitors (HS94 and HS148) were developed to provide mechanistic insight into the polypharmacology of hypertension. In vitro and ex vivo studies indicated that Pim kinases directly phosphorylate smooth muscle targets and that Pim/DAPK3 inhibition, unlike selective DAPK3 inhibition, significantly reduces contractility. In vivo, HS56 decreased blood pressure in spontaneously hypertensive mice in a dose-dependent manner without affecting heart rate. These findings suggest including Pim kinase inhibition within a multi-target engagement strategy for hypertension management. HS56 represents a significant step in the development of molecularly targeted antihypertensive medications.
Authors
Carlson, DA; Singer, MR; Sutherland, C; Redondo, C; Alexander, LT; Hughes, PF; Knapp, S; Gurley, SB; Sparks, MA; MacDonald, JA; Haystead, TAJ
MLA Citation
Carlson, David A., et al. “Targeting Pim Kinases and DAPK3 to Control Hypertension.Cell Chem Biol, vol. 25, no. 10, Oct. 2018, pp. 1195-1207.e32. Pubmed, doi:10.1016/j.chembiol.2018.06.006.
URI
https://scholars.duke.edu/individual/pub1331120
PMID
30033129
Source
pubmed
Published In
Cell Chem Biol
Volume
25
Published Date
Start Page
1195
End Page
1207.e32
DOI
10.1016/j.chembiol.2018.06.006

Cryo-sectioned mice for investigating HS-131 uptake

Data related to submitted manuscript “A far-red Hsp90 inhibitor reveals mechanism underlying external Hsp90 trafficking”. Brightfield and fluorescence images of an experimental mouse (721 images each) and control mouse (620 images each).
Authors
Crowe, LB; Hughes, PF; Acorta, DA; Osada, T; Smith, AP; Totke, J; Loiselle, DR; Gargesha, M; Roy, D; Lyerly, HK; Spector, NL; Haystead, T
MLA Citation
Crowe, Lauren B., et al. Cryo-sectioned mice for investigating HS-131 uptake. 18 July 2016. Manual, doi:10.7924/G8G44N63.
URI
https://scholars.duke.edu/individual/pub1383070
Source
manual
Published Date
DOI
10.7924/G8G44N63

A highly selective Hsp90 affinity chromatography resin with a cleavable linker.

Over 200 proteins have been identified that interact with the protein chaperone Hsp90, a recognized therapeutic target thought to participate in non-oncogene addiction in a variety of human cancers. However, defining Hsp90 clients is challenging because interactions between Hsp90 and its physiologically relevant targets involve low affinity binding and are thought to be transient. Using a chemo-proteomic strategy, we have developed a novel orthogonally cleavable Hsp90 affinity resin that allows purification of the native protein and is quite selective for Hsp90 over its immediate family members, GRP94 and TRAP 1. We show that the resin can be used under low stringency conditions for the rapid, unambiguous capture of native Hsp90 in complex with a native client. We also show that the choice of linker used to tether the ligand to the insoluble support can have a dramatic effect on the selectivity of the affinity media.
Authors
Hughes, PF; Barrott, JJ; Carlson, DA; Loiselle, DR; Speer, BL; Bodoor, K; Rund, LA; Haystead, TAJ
MLA Citation
Hughes, Philip F., et al. “A highly selective Hsp90 affinity chromatography resin with a cleavable linker.Bioorg Med Chem, vol. 20, no. 10, May 2012, pp. 3298–305. Pubmed, doi:10.1016/j.bmc.2012.03.043.
URI
https://scholars.duke.edu/individual/pub776049
PMID
22520629
Source
pubmed
Published In
Bioorg Med Chem
Volume
20
Published Date
Start Page
3298
End Page
3305
DOI
10.1016/j.bmc.2012.03.043