Presentation on theme: "1 Development and Screening of Transition Metal Complexes as CXCR4 Antagonists Dr. Tim Hubin Department of Chemistry and Physics Sept. 10, 2009 INBRE Steering."— Presentation transcript:
1 Development and Screening of Transition Metal Complexes as CXCR4 Antagonists Dr. Tim Hubin Department of Chemistry and Physics Sept. 10, 2009 INBRE Steering Committee
2 CXCR4 chemokine receptor Important role in embryonic development: – Organogenesis (liver, heart) – Stem cell movement – Cerebellar neuron migration (formation of brain) Seven transmembrane G- protein-coupled receptor 27% of amino acids are Asp, His or Tyr. Expressed on : » Leukocytes » T-lymphocytes » Endothelial cells » Neuronal cells Khan, A.; Greenman, J.; Archibald, S. J. Curr. Med. Chem. 2007, 14, 2257.
3 CXCL12 67 residue highly basic protein Only known natural ligand (chemokine) for CXCR4 Secreted by stromal, lung and liver cells, and lymph nodes Attracts leukocytes to sites of inflammation and lymphoid organs
4 Disease states Role in disease – Human Immunodeficiency Virus – Tumour growth and metastasis – Stem cell mobilization – Autoimmune disorders (rheumatoid arthritis)
5 Inhibitors against 5 steps of HIV replication cycle Still need for new targets CXCR4-antagonists Prototype bicyclams AMD3100
7 Blocking receptor functions Cell Drug CXCL12/HIV
8 Over expression of CXCR4 receptors Normal cell Cancer cell
9 CXCR4 antagonists Peptide based Side chains protonated at physiological pH
10 Plerixafor/ AMD3100 AMD3100 The first bicyclams were discovered as impurities in a sample of cyclam. Amongst the most active anti-HIV agents in vitro. Anti-HIV clinical testing discontinued. Stem cell mobilization For example: Mol. Pharm., 1999, 55, 67. J. Med. Chem., 1995, 38, 366. Biochemistry, 2003, 42, 715.
11 Molecular shape Bosnich, B.; Poon, C. K.; Tobe, M. L. Inorg. Chem.,1965, 4,1102
27 Control Drug/ no CXCL12 CXCL12 Drug + CXCL12
28 CONCLUSIONS Axial vs. equatorial coordination makes all the difference in copper(II) containing protein binding drugs. Promising early anti-metastatic properties in vitro. In vivo testing to follow.
29 Acknowledgements Funding – OK-INBRE (NIH) – Research Corporation – SWOSU Dr. Steve Archibald (Hull) Abid Khan Prof. Erik De Clercq (Leuven) Dr. Christophe Pannecouque(Leuven) Dr. Dominique Schols (Leuven) Prof Tony Ng (KCL) Current research group: Courtney Garcia (Pre-Med) Josh Priddle (Pre-Med) Desiray Cannon (Pre-Med) Brooke Shockey (Pre-Med) Katherine Coats (Chemistry) Past members: Robert Ullom—University of Kansas (Medicine) TauLyn Snell—Wichita State University (PA) Joe Blas—Creighton (Medicine) Danny Maples—OSU (Chemistry) Randall Maples—OSU (Chemistry) Dallas Matz—Arizona State University (Chemistry) Mike McClain—OU (Chemistry) Amy Cain—U. British Columbia (Chemistry) Neil Funwie—OU (Petroleum Engineering) Orry Birdsong—UT Galveston (Medicine) Kimberly Roewe—OSU (Chemistry) Kiet Ngyuen—SWOSU (Pharmacy)