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tim_willson

Tim Willson

Professor

Tim Willson, Ph.D.

Professor, SGC Center for Chemical Biology


tim_willson

PHONE
(919) 491-3177
EMAIL
tim.willson@unc.edu
ADDRESS
1062 Genetic Medicine Buildin, 120 Mason Farms Road, CB# 7356, Chapel Hill, NC, 27599
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The Willson laboratory is home to the U.S. site of the Structural Genomics Consortium (SGC), an open science public-private partnership that accelerates research on the lesser studied regions of the genome. The SGC‑UNC laboratory works closely with pharma companies and academic investigators to develop small molecule chemical probes of the dark proteome that are openly shared with the scientific community. Current research has led to the development of the Kinase Chemogenomic Set (KCGS) that contains selective inhibitors of more than 200 dark kinases. SGC‑UNC scientists are experts in medicinal chemistry, cell biology, and chemical biology.

 

Current SGC-UNC research programs include:

  • Development of chemical probes and NanoBRET assays for dark kinases in support of the Illuminating the Druggable Genome consortium
  • Development of chemical probes for viral pathogens of pandemic potential for the READDI Antiviral Drug Discovery Center
  • Development of chemical probes to validate proteins associated with Alzheimer’s disease for the TREAT-AD consortium

Description

Willson has been a long-time supporter of precompetitive chemistry as a mechanism to bring innovation to early drug discovery. His team has made potent and selective chemical probes for orphan nuclear receptors widely available in the scientific community. He was a scientific founder of the SGC Epigenetic Chemical Probes project that led to the release into the public domain of more than 30 chemical probes that specifically inhibit enzyme modifiers and protein readers of the histone tails. Willson started a program to develop chemical probes for the understudied protein kinases that has made a set of  more than 800 kinase inhibitors freely available to academic researchers. The open availability of these chemical probes has had widespread scientific impact through their use as tools to study the biology of their cognate proteins.

Citations

  1. Edwards AM, Bountra C, Kerr DJ, Willson TM. Open access chemical and clinical probes to support drug discovery. Nat Chem Biol. 2009 Jul;5(7):436-40. PubMed PMID: 19536100.
  2. Edwards AM, Isserlin R, Bader GD, Frye SV, Willson TM, Yu FH. Too many roads not taken. Nature. 2011 Feb 10;470(7333):163-5. PubMed PMID: 21307913.
  3. Knapp S, Arruda P, Blagg J, Burley S, Drewry DH, Edwards A, Fabbro D, Gillespie P, Gray NS, Kuster B, Lackey KE, Mazzafera P, Tomkinson NC, Willson TM, Workman P, Zuercher WJ. A public-private partnership to unlock the untargeted kinome. Nat Chem Biol. 2013 Jan;9(1):3-6. PubMed PMID: 23238671.
  4. Drewry DH, Willson TM, Zuercher WJ. Seeding collaborations to advance kinase science with the GSK Published Kinase Inhibitor Set (PKIS). Curr Top Med Chem. 2014;14(3):340-2. PubMed PMID: 24283969; PubMed Central PMCID: PMC4435035.

Description

Willson led a team of scientists that uncovered the role of orphan nuclear receptors in human metabolism. Two key discoveries were the role of PPARg as the receptor for the TZD diabetes drugs, and the role of bile acids as the natural hormones for FXR that led to the development of OCA as a breakthrough drug for treatment of liver disorders. The team designed a scientific methodology known as reverse endocrinology in which chemical probes are used to uncover the basic biology of their target receptor in a disease agnostic manner. This strategy has found application in many other protein families, including GPCRs, protein kinases and the epigenetic modifiers of histone tails.

Citations

  1. Kliewer SA, Lehmann JM, Willson TM. Orphan nuclear receptors: shifting endocrinology into reverse. Science. 1999 Apr 30;284(5415):757-60. PubMed PMID: 10221899.
  2. Maloney PR, Parks DJ, Haffner CD, Fivush AM, Chandra G, Plunket KD, Creech KL, Moore LB, Wilson JG, Lewis MC, Jones SA, Willson TM. Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem. 2000 Aug 10;43(16):2971-4. PubMed PMID: 10956205.
  3. Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5306-11. PubMed PMID: 11309497; PubMed Central PMCID: PMC33205.
  4. Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, Morelli A, Parks DJ, Willson TM. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002 Aug 15;45(17):3569-72. PubMed PMID: 12166927.

Publications


  • Comprehensive characterization of the Published Kinase Inhibitor Set. Elkins JM, Fedele V, Szklarz M, Abdul Azeez KR, Salah E, Mikolajczyk J, Romanov S, Sepetov N, Huang XP, Roth BL, Al Haj Zen A, Fourches D, Muratov E, Tropsha A, Morris J, Teicher BA, Kunkel M, Polley E, Lackey KE, Atkinson FL, Overington JP, Bamborough P, Müller S, Price DJ, Willson TM, Drewry DH, Knapp S, Zuercher WJ. Nat Biotechnol. 2016 Jan;34(1):95-103. doi: 10.1038/nbt.3374. Epub 2015 Oct 26. PMID: 26501955
  • Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B. Chen P, Chaikuad A, Bamborough P, Bantscheff M, Bountra C, Chung CW, Fedorov O, Grandi P, Jung D, Lesniak R, Lindon M, Müller S, Philpott M, Prinjha R, Rogers C, Selenski C, Tallant C, Werner T, Willson TM, Knapp S, Drewry DH. J Med Chem. 2016 Feb 25;59(4):1410-24. doi: 10.1021/acs.jmedchem.5b00209. Epub 2015 Apr 6. PMID: 25799074

  • The promise and peril of chemical probes. Arrowsmith CH, Audia JE, Austin C, Baell J, Bennett J, Blagg J, Bountra C, Brennan PE, Brown PJ, Bunnage ME, Buser-Doepner C, Campbell RM, Carter AJ, Cohen P, Copeland RA, Cravatt B, Dahlin JL, Dhanak D, Edwards AM, Frederiksen M, Frye SV, Gray N, Grimshaw CE, Hepworth D, Howe T, Huber KV, Jin J, Knapp S, Kotz JD, Kruger RG, Lowe D, Mader MM, Marsden B, Mueller-Fahrnow A, Müller S, O’Hagan RC, Overington JP, Owen DR, Rosenberg SH, Roth B, Ross R, Schapira M, Schreiber SL, Shoichet B, Sundström M, Superti-Furga G, Taunton J, Toledo-Sherman L, Walpole C, Walters MA, Willson TM, Workman P, Young RN, Zuercher WJ. Nat Chem Biol. 2015 Aug;11(8):536-41. doi: 10.1038/nchembio.1867. No abstract available. Erratum in: Nat Chem Biol. 2015 Nov;11(11):887. Nat Chem Biol. 2015 Aug;11(8):541. Roth, Brian [Corrected to Roth, Bryan] and Frederiksen, Mathias [Added

  • Optimized chemical probes for REV-ERBα. Trump RP, Bresciani S, Cooper AW, Tellam JP, Wojno J, Blaikley J, Orband-Miller LA, Kashatus JA, Boudjelal M, Dawson HC, Loudon A, Ray D, Grant D, Farrow SN, Willson TM, Tomkinson NC. J Med Chem. 2013 Jun 13;56(11):4729-37. doi: 10.1021/jm400458q. Epub 2013 May 23. PMID: 23656296
  • A public-private partnership to unlock the untargeted kinome. Knapp S, Arruda P, Blagg J, Burley S, Drewry DH, Edwards A, Fabbro D, Gillespie P, Gray NS, Kuster B, Lackey KE, Mazzafera P, Tomkinson NC, Willson TM, Workman P, Zuercher WJ. Nat Chem Biol. 2013 Jan;9(1):3-6. doi: 10.1038/nchembio.1113. No abstract available. PMID: 23238671

  • Synthesis and anti-HIV-l activity in a series of imidazo[1,5-b]pyridazines.  D. G. H. Livermoore, R. C. Bethell, N. Cammack, A. P. Handcock, M. M. Hann, D. V. S. Green, R. B. Lamont, S. A. Noble, D. C. Orr, J. J. Payne, M. V. J. Ramsay, A. H. Shingler, C. Smith, R. Storer, C. Williamson, and T. M. Willson. J. Med. Chem., 1993 36 3784-3794.
  • L-696,986: a functionally selective and potent muscarinic M1 receptor partial agonist.  G. A. Showell, R. Baker, S. Connolly, R. J. Snow, I. Stansfield, T. Willson, R. J. Hargreaves, K. Woodford, S. Patel, and S. B. Freedman. Med. Chem. Res., 1993 3 171-177.

  • Synthesis and muscarinic activity of quinuclidinyl- and (1-azanorbornyl)pyrazine derivatives.  L. J. Street, R. Baker, T. Book, A. J. Reeve, J. Saunders, T. Willson, R. S. Marwood, S. Patel, and S. B. Freedman. J. Med. Chem., 1992 35 295-305.

  • Synthesis of - and -branched ethers from alcohols by reaction of acetals with Grignard reagents: synthesis of isopropyl and isobutyl ethers of (1S*,2R*S*,4R*)-6-methylenebicyclo[2.2.2]octan-2-ol.  T. M. Willson, J. Amburgey, and S. E. Denmark. J. Chem. Soc., Perkin Trans. 1, 1991 2899-2906.

  • A synthesis of (+)-pederin, the metalated dihydropyran approach.  J. Krzysztof, P. Kocienski, S. Marczak,  and T. Willson. Tetrahedron Lett., 1990 31 3433-3436.
  • Studies related to the synthesis of (±)-pederin. Part 2. Synthesis of pederol dibenzoate and benzoylpedamide.  T. M. Willson, P. Kocienski, K. Jarowicki, K. Isaac, P. M. Hitchcock, A. Faller, and S. F. Campbell. Tetrahedron, 1990 46 1767-1782.
  • Studies related to the synthesis of (±)-pederin. Part 1. Synthesis of ethyl pederate and benzoylselenopederic acid.  T. M. Willson, P. Kocienski, K. Jarowicki, K. Isaac, A. Faller, S. F. Campbell, and J. Bordner. Tetrahedron, 1990 46 1757-1767.

  • Mechanistic and stereochemical divergence in the allylsilane-acetal addition reaction.  E. Denmark and T. M. Willson. J. Am. Chem. Soc., 1989 111 3475-3476.
  • Studies on the mechanism of allylmetal-acetal additions.  S. E. Denmark and T. M. Willson. NATO ASI Ser., Ser. C, 1989 289 247-263.
  • Stereochemical and spectroscopic studies on the reaction of allylstannanes with aldehydes.  S. E. Denmark, E. J. Weber, T. M. Wilson, and T. M. Willson. Tetrahedron, 1989 45 1053-1065.

  • On the Lewis acid-induced addition of allylstannanes to aldehydes: a spectroscopic investigation.  S. E. Denmark, T. Wilson, and T. M. Willson. J. Am. Chem. Soc., 1988 110 984-986.

  • The total synthesis of (±)-pederin.  T. Willson, P. Kocienski, A. Faller, and S. Campbell. J. Chem. Soc., Chem. Commun., 1987 106-108.

  • Synthetic approaches to pederin. A synthesis of (±)‑benzoylpedamide.  P. Kocienski and T. M. Willson. J. Chem. Soc., Chem. Commun., 1984 1011-1012.

Select Book Chapters


  • A. Kliewer and T. M. Willson. Identification of ligands for orphan nuclear receptors, in Handbook of Cell Signaling. Vol. 3.  Ed. R. A. Bradshaw and E. A. Dennis, Elsevier, San Diego, CA, 2004, p. 53-55.
  • M. Willson, M. H. Lambert, and H. E. Xu. Design, structure, and function of novel PPAR ligands, in Peroxisome Proliferator Activated Receptors: from Basic Science to Clinical Applications.  Ed. J.-C. Fruchart, A. M. Gotto, Jr., R. Paoletti, B. Steals, and A. L. Catapano, Kluwer Academic Publications, Dordrecht, The Netherlands, 2002, p. 5-8.
  • Oliver, Jr., D. Sternbach, B, Hansen, and T. Willson. Pharmacology of a selective peroxisome proliferator-activated receptor  agonist, GW501516, in obese dyslipidemic primates, in Peroxisome Proliferator Activated Receptors: from Basic Science to Clinical Applications.  Ed. J.-C. Fruchart, A. M. Gotto, Jr., R. Paoletti, B. Steals, and A. L. Catapano, Kluwer Academic Publications, Dordrecht, The Netherlands, 2002, p. 131-134.
  • Hunt, N. Pearson, T. M. Willson, and A. Takle. Intracellular targets, in Medicinal Chemistry (2nd Edition).  Ed. F. D. King, Royal Society of Chemistry, Cambridge, UK, 2002, p. 42-63.
  • T. Moore, T. M. Willson, and S. A. Kliewer. The physiological role of prenane-X-receptor (PXR) in xenobiotic and bile acid homeostasis, in Comprehensive Toxicology. Volume 14: Cellular and Molecular Toxicology.  Ed. J. P. Vanden Heuvel, G. H. Perdew, W. B. Mattes, and W. F. Greenlee, Elsevier Science, New York, NY, 2002, p. 159-172.
  • M. Willson. Chemistry: structure and function relationships, in Estrogens Antiestrogens.  Ed. R. Lindsay, D. W. Dempster, and V. C. Jordan, Lippincott-Raven, Philadelphia, PA, 1997, p. 21-28.
  • Kocienski, K. Jarowicki, S. Marczak, and T. M. Willson. Three and one-half approaches to the synthesis of pederin, in Strategies and Tactics in Organic Synthesis.  Ed. T. Lindberg.  Academic Press, San Diego, CA. 1991, p. 199-236

Positions and Employment

1990-1991: Research Scientist, Merck Sharp $ Dohme, Harlow, UK

1991-2015: Director of Chemical Biology, GlaxoSmithKline, Research Triangle Park, NC, USA

2015: Research Professor, University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, NC, USA

Other Experience and Professional Memberships

1988: Member, American Chemical Society

Education

INSTITUTION AND LOCATION DEGREE  YEAR FIELD OF STUDY
University of Leeds, Leeds, Yorkshire, UK BACHELOR OF SCIENCE      83      Chemistry
University of Southampton, Southampton, Hampshire, UK DOCTOR OF PHILOSOPHY     86     Organic Chemistry
University of Illinois at Urbana-Champaign, Champaign, IL Postdoctoral Fellow      88      Organic Chemistry


Structural Genomics Consortium Grant Funding