|Home||PCB at Duke||Faculty||Graduate Programs||Undergraduate Program||Postdoctoral Program||Seminar Series||Summer Research||Annual Retreat|
Professor of Pharmacology and Cancer Biology
Duke University School of Medicine
Durham, NC 27710
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. 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 TNFα, IL1 and TGFβ. The foundations of these programs are based on the development a chemoproteomic strategy utilizing affinity methods combined with in house organic synthetic chemistry.
Fasnall, a Selective FASN Inhibitor, Shows Potent Anti-tumor Activity in the MMTV-Neu Model of HER2(+) Breast Cancer. Alwarawrah Y, Hughes P, Loiselle D, Carlson DA, Darr DB, Jordan JL, Xiong J, Hunter LM, Dubois LG, Thompson JW, Kulkarni MM, Ratcliff AN, Kwiek JJ, Haystead TA. Cell Chem Biol. 2016 Jun 23;23(6):678-88.
Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70. Howe MK, Bodoor K, Carlson DA, Hughes PF, Alwarawrah Y, Loiselle DR, Jaeger AM, Darr DB, Jordan JL, Hunter LM, Molzberger ET, Gobillot TA, Thiele DJ, Brodsky JL, Spector NL, Haystead TA. Cell. Chem Biol. 2014 Dec 18;21(12):1648-59.
Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor. Carlson DA, Franke AS, Weitzel DH, Speer BL, Hughes PF, Hagerty L, Fortner CN, Veal JM, Barta TE, Zieba BJ, Somlyo AV, Sutherland C, Deng JT, Walsh MP, MacDonald JA, Haystead TA. ACS Chem Biol. 2013 Dec 20;8(12):2715-23.
Optical and radioiodinated tethered Hsp90 inhibitors reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells. Barrott JJ, Hughes PF, Osada T, Yang XY, Hartman ZC, Loiselle DR, Spector NL, Neckers L, Rajaram N, Hu F, Ramanujam N, Vaidyanathan G, Zalutsky MR, Lyerly HK, Haystead TA. Cell Chem Biol. 2013 Sep 19;20(9):1187-97
A highly selective Hsp90 affinity chromatography resin with a cleavable linker. Hughes PF, Barrott JJ, Carlson DA, Loiselle DR, Speer BL, Bodoor K, Rund LA, Haystead TA. Bioorg Med Chem. 2012 May 15;20(10):3298-305.
Application of chemoproteomics to drug discovery: identification of a clinical candidate targeting hsp90. Fadden P, Huang KH, Veal JM, Steed PM, Barabasz AF, Foley B, Hu M, Partridge JM, Rice J, Scott A, Dubois LG, Freed TA, Silinski MA, Barta TE, Hughes PF, Ommen A, Ma W, Smith ED, Spangenberg AW, Eaves J, Hanson GJ, Hinkley L, Jenks M, Lewis M, Otto J, Pronk GJ, Verleysen K, Haystead TA. Hall S Cell. Chem Biol. 2010 Jul 30;17(7):686-94.