1 Development and Screening of Transition Metal Complexes as CXCR4 Antagonists Dr. Tim Hubin Department of Chemistry and Physics Sept. 10, 2009 INBRE Steering.

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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

6 Gerlach et al., 2001

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

12

13 Restrict to one configuration Only trans Only cis V

14 Side-Bridged Synthesis Reagents: (a) acetonitrile, RT, 24 h (89%); (b) NaBH 4, EtOH reflux, 1 h (65%).

15 Cross-Bridged Synthesis

16 AMD3100 Lewis, E. A.; Hubin, T. J.; Archibald, S. J. European Patent A2.

17 Copper(II) coordination AxialEquatorial

18 COMPLEX CHARACTERISATION

19 Cu-O12.28(1) Å Side bridged (SB) Cross bridged (CB) Cu-O11.95(1) Å AxialEquatorial

20

21 Selecting the cell line Use anti-CXCR4 antibodies to screen cell lines Two identified Jurkat and Molt-4 Four anti-CXCR4 antibodies used (variation in binding epitopes)

22 Binding by flow cytometry CXCR4 Drug molecule Receptor specific antibody Fluorescent antibody KeyNameParameter - control.001FL1-H + Control FL1-H L FL1-H L FL1-H

23 Summary of mAb 12G5 binding to CXCR4 in the presence of bound antagonists.

24 Residence time G. McRobbie, A. Khan, G. Nicholson, L. Madden, J. Greenman C. Pannecouque, E. De Clercq, T. J. Hubin and S. J. Archibald, J. Am. Chem. Soc, 2009, 3416.

25 Invasion assays Cell invasion assays in response to a chemokine gradient. Initially used SJSA cells. Experiments run in presence and absence of antagonist. ANTI-CANCER ACTIVITY

26 Invasive CXCR4 mutants

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)