Xiaodong Wang, PhD

Director of Medicinal Chemistry, CICBDD Research Associate Professor

Research

Drug Discovery

The majority of cellular pathways, especially those involved in signal transduction, are regulated by kinases. Kinases are proteins that can modify other proteins by phosphorylation at one of three amino acids that have a free hydroxyl group. Phorsphorylation results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. Inappropriate kinase expression and activity is a frequent cause of disease, in particular cancer. Small molecule inhibitors have been introduced into the clinic for treatment of certain cancers. We are currently focused on developing small molecule Mer inhibitors as clinical candidates to treat pediatric acute lymphoblastic leukemia. We are also interested in other kinases such as IKKepsilon/TBK1 and ROR2.

Synthetic Methodology Development

Heterocyclic compounds are widely used in drug discovery as synthetic pharmacophores. However, some are not readily available and are difficult to prepare in the variety and quantities needed for structure-activity relationship studies. We are currently interested in developing short, effective and robust synthetic routes to prepare heterocycles such as pyrazolopyrimidines and pyrrolopyrimidines.

Education, Certification and Licensure

1997–2002 PhD in Organic Chemistry, University of Pittsburgh (Pittsburgh, PA)

2002–2004 Staff Scientist, Lead Generation and Lead Optimization, Array BioPharma (Boulder, CO)

2004–2006 Research Scientist, Lead Optimization, Array BioPharma (Boulder, CO)

2006–2007 Research Investigator I, Department of Medicinal Chemistry, Genomic Institute of the Novartis Research Foundation (San Diego, CA)

2008–         Research Assistant Professor, Division of Medicinal Chemistry, Eshelman School of Pharmacy

2008–2014  Assistant Director of Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

2014-          Director of Medicinal Chemistry, Center for Integrative Chemical Biology and Drug Discovery

Publications

  • Zhang, W.; DeRyckere, D.; Hunter, D.; Liu, J.; Stashko, M. A.; Minson, K. A.; Cummings, C. T.; Lee, M.; Glaros, T. G.; Newton, D. L.; Sather, S.; Zhang, D.; Kireev, D.; Janzen, W. P.; Earp, H. S.; Graham, D. K.; Frye, S. V.; Wang, X., UNC2025, a Potent and Orally Bioavailable MER/FLT3 Dual Inhibitor. J. Med. Chem. 2014. 57 (16), 7031-7041.
  • Zhang, W.; McIver, A. L.; Stashko, M. A.; Deryckere, D.; Branchford, B. R.; Hunter, D.; Kireev, D.; Miley, M. J.; Norris-Drouin, J.; Stewart, W. M.; Lee, M.; Sather, S.; Zhou, Y.; Di Paola, J. A.; Machius, M.; Janzen, W. P.; Earp, H. S.; Graham, D. K.; Frye, S. V.; Wang, X.*  Discovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of Thrombosis. J Med Chem 2013. 56 (23), 9693-9700.
  • Zhang, W.; Zhang, D.; Stashko, M. A.; Deryckere, D.; Hunter, D.; Kireev, D.; Miley, M. J.; Cummings, C.; Lee, M.; Norris-Drouin, J.; Stewart, W. M.; Sather, S.; Zhou, Y.; Kirkpatrick, G.; Machius, M.; Janzen, W. P.; Earp, H. S.; Graham, D. K.; Frye, S. V.; Wang, X.* Pseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors. J Med Chem 2013. 56 (23), 9683-9692.
  • Christoph, S.; DeRyckere, D.; Schlegel, J.; Frazer, J. K.; Batchelor, L. A.; Trakhimets, A. Y.; Sather, S.; Hunter, D. M.; Cummings, C. T.; Liu, J.; Yang, C.; Kireev, D.; Simpson, C.; Norris-Drouin, J.; Hull-Ryde, E. A.; Janzen, W. P.; Johnson, G. L.; Wang, X.; Frye, S. V.; Earp III, H. S.; Graham, D. K., UNC569, a Novel Small-Molecule Mer Inhibitor with Efficacy against Acute Lymphoblastic Leukemia In Vitro and In Vivo. Mol. Cancer Therap. 2013, 12 (11), 2367-2377.
  • Liu, J.; Zhang, W.; Stashko, M. A.; DeRyckere, D.; Cummings, C.T.; Hunter, D.; Yang, C.; Jayakody, C. N.; Cheng, N.; Simpson, C.; Norris-Drouin, J.; Sather, S.; Kireev, D.; Janzen, W. P.; Earp, H. S., Graham, D. K.; Frye, S. V.; and Wang, X.*  UNC1062, a new and potent Mer inhibitor.  Eur. J. Med. Chem. 2013, 65 (0), 83-93.
  • Schlegel, J.; Sambade, M. J.; Sather, S.; Moschos, S. J.; Tan, A. C.; Winges, A.; Deryckere, D.; Carson, C. C.; Trembath, D. G.; Tentler, J. J.; Eckhardt, S. G.; Kuan, P. F.; Hamilton, R. L.; Duncan, L. M.; Miller, C. R.; Nikolaishvili-Feinberg, N.; Midkiff, B. R.; Liu, J.; Zhang, W.; Yang, C.; Wang, X.; Frye, S. V.; Earp, H. S.; Shields, J. M.; Graham, D. K., MERTK receptor tyrosine kinase is a therapeutic target in melanoma. The Journal of Clinical Investigation 2013, 123 (5), 2257-2267.
  • Zhang, W.; Liu, J.; Stashko, M. A.; Wang, X.* Efficient Solution-Phase Synthesis of 4,5,7-Trisubstituted Pyrrolo[3,2-d]pyrimidines. ACS Combinatorial Science 2012, 15 (1), 10-19.
  • Hutti, J. E.; Porter, M. A.; Cheely, A. W.; Cantley, L. C.; Wang, X.; Kireev, D.; Baldwin, A. S.; Janzen, W. P., Development of a High-Throughput Assay for Identifying Inhibitors of TBK1 and IKKepsilon. PloS one 2012, 7 (7), e41494.
  • Liu, J.; Yang, C.; Simpson, C.; DeRyckere, D.; Van, D. A.; Miley, M. J.; Kireev, D.; Norris-Drouin, J.; Sather, S.; Hunter, D.; Korboukh, V. K.; Patel, H. S.; Janzen, W. P.; Machius, M.; Johnson, G. L.; Earp, H. S.; Graham, D. K.; Frye, S. V.; Wang, X.* “Discovery of Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia”,  ACS Med. Chem. Lett. 2012, 3, 129-134.
  • Liu, J.; Wang, X.* “Microwave-Assisted, Divergent Solution-Phase Synthesis of 1,3,6-Trisubstituted Pyrazolo[3,4-d]pyrimidines”, ACS Combinatorial Science 2011, 13 (4), 414-420.