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Timothy Haystead

Associate Professor
Pharmacology and Cancer Biology
919-613-8606
Research Interest: 
Enzymology
Molecular structure
Signal transduction
Research Summary: 
Smooth and striated muscle plasticity in response to physiological stress, drug discovery in obesity, and drug discovery in infectious diseases.
Research Description: 

Smooth and striated muscle plasticity and signaling.
In this work we have used a combination of classical physiological and chemoproteomics to define several novel regulatory subunits governing smooth and striated muscle plasticity. Using proteomic methods to study signaling pathways in vivo we discovered Smoothelin Like Protein 1 (SMTNL1). After developing smntl1-/- mice, we showed the importance of SMTNL1 in regulating the expression of myosin phosphatase in smooth and striated muscle and believe it to be a key mediator regulating muscle plasticity during pregnancy and exercise. Indeed, in striated muscle we believe that during pregnancy SMTNL1, acting through the progesterone receptor, mediates switching of striated muscle to a glycolytic phenotype. We hypothesize that this pathway is an evolutionary adaptation to pregnancy and underlies increased weight gain and insulin resistance in pregnant women. Additionally we characterized several protein kinase mediated pathways that regulate myosin phosphatase activity, including discovery of zipper interacting protein kinase (ZIPK). We are currently developing a novel panel of highly selective ZIPK inhibitors using novel chemoproteomic technology developed in my laboratory.

Drug discovery in obesity and in infectious diseases.
One of the underpinnings of my laboratory is technology development which has greatly enabled our drug discovery programs. In the course of characterizing signaling events in muscle, we developed several novel affinity tools and protein sequencing methodologies. These tools were rapidly developed into a drug discovery platform, proteome mining. From its conception it was obvious that proteome mining should be commercialized to realize its drug discovery potential. In 2000 I founded the Durham based company Serenex Inc. During its 8 year life time Serenex employed over 50 scientists and business people. In 2008 the company was purchased by Pfizer for its drug SNX5422. SNX5422 was discovered and developed by Serenex as is an orally bioavailable inhibitor of HSP90 with multiple indications in cancer. To date the drug has completed several Phase 1 trials conducted by Pfizer and the NCI. The formation of Serenex exposed me to the world of medicinal chemistry and allowed me to bring this discipline back into my own academic laboratory. We are currently applying to the technology to develop a series of paramagnetic and fluorescent Hsp90 inhibitors for cancer imaging. We are also using the same technology to develop a series of novel inhibitors targeting the pathways of de novo fatty acid synthesis as novel therapeutics for the treatment of obesity and Type II diabetes. Targets include ATP citrate lyase, Acetyl CoA carboxylase, Fatty acid synthase and AMP kinase. Our recent interest in infectious disease was very much driven by a natural fit of our technology platform to discovering novel antibiotics and antiviral agents. I am particularly attracted to this arena because of the many testable models for target validation, contrasting with many other drug discovery problems in which physiological relevant models of disease are not so robust.

Publications: 
Smoothelin-like 1 protein is a bifunctional regulator of the progesterone receptor during pregnancy.
Bodoor K, Lontay B, Safi R, Weitzel DH, Loiselle D, Wei Z, Lengyel S, McDonnell DP, Haystead TA.
J Biol Chem. 2011. 286:31839-51.

Phosphorylation-dependent control of ZIPK nuclear import is species specific.
Weitzel DH, Chambers J, Haystead TA.
Cell Signal. 2011. 23:297-303.

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 SE.
Chem Biol. 2010. 17:686-94.

Smoothelin-like 1 protein regulates myosin phosphatase-targeting subunit 1 expression during sexual development and pregnancy.
Lontay B, Bodoor K, Weitzel DH, Loiselle D, Fortner C, Lengyel S, Zheng D, Devente J, Hickner R, Haystead TA.
J Biol Chem. 2010. 285:29357-66.

Deletion of the protein kinase A/protein kinase G target SMTNL1 promotes an exercise-adapted phenotype in vascular smooth muscle.
Wooldridge AA, Fortner CN, Lontay B, Akimoto T, Neppl RL, Facemire C, Datto MB, Kwon A, McCook E, Li P, Wang S, Thresher RJ, Miller SE, Perriard JC, Gavin TP, Hickner RC, Coffman TM, Somlyo AV, Yan Z, Haystead TA.
J Biol Chem. 2008. 283:11850-9.