Development and screening of transition metal complexes as cxcr4 antagonists
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Sept. 10, 2009 INBRE Steering Committee. Development and Screening of Transition Metal Complexes as CXCR4 Antagonists. Dr. Tim Hubin Department of Chemistry and Physics. Important role in embryonic development: Organogenesis (liver , heart) Stem cell movement

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Development and screening of transition metal complexes as cxcr4 antagonists l.jpg

Sept. 10, 2009 INBRE Steering Committee

Development and Screening of Transition Metal Complexes as CXCR4 Antagonists

Dr. Tim Hubin

Department of Chemistry and Physics


Cxcr4 chemokine receptor l.jpg

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

CXCR4 chemokine receptor

Khan, A.; Greenman, J.; Archibald, S. J. Curr. Med. Chem. 2007, 14, 2257.


Cxcl12 l.jpg
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


Disease states l.jpg
Disease states

  • Role in disease

    • Human Immunodeficiency Virus

    • Tumour growth and metastasis

    • Stem cell mobilization

    • Autoimmune disorders (rheumatoid arthritis)


Slide5 l.jpg



Blocking receptor functions l.jpg
Blocking receptor functions

CXCL12/HIV

Drug

Cell


Over expression of cxcr4 receptors l.jpg
Over expression of CXCR4 receptors

Cancer cell

Normal cell


Cxcr4 antagonists l.jpg
CXCR4 antagonists

  • Peptide based

  • Side chains

    protonated at

    physiological pH


Plerixafor amd3100 l.jpg
Plerixafor/ 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.

AMD3100


Molecular shape l.jpg
Molecular shape

Bosnich, B.; Poon, C. K.; Tobe, M. L. Inorg. Chem.,1965, 4,1102


Restrict to one configuration l.jpg
Restrict to one configuration

Only cis V

Only trans


Side bridged synthesis l.jpg
Side-Bridged Synthesis

Reagents: (a) acetonitrile, RT, 24 h (89%); (b) NaBH4, EtOH reflux, 1 h (65%).


Slide15 l.jpg

Cross-BridgedSynthesis


Slide16 l.jpg

AMD3100

Lewis, E. A.; Hubin, T. J.; Archibald, S. J. European Patent 1765826A2 .


Copper ii coordination l.jpg
Copper(II) coordination

Axial

Equatorial



Slide19 l.jpg

Side bridged (SB)

Cross bridged (CB)

Axial

Equatorial

Cu-O1 2.28(1) Å

Cu-O1 1.95(1) Å


Selecting the cell line l.jpg
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)


Binding by f low cytometry l.jpg

Key

Name

Parameter

- control.001

FL1-H

+ Control 717.019

FL1-H

L2 717.010

FL1-H

L1 717.009

FL1-H

Binding by flow cytometry

Fluorescent antibody

Receptor specific antibody

Drug molecule

CXCR4



Residence time l.jpg
Residence time bound antagonists.

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.


Invasion assays l.jpg

ANTI-CANCER ACTIVITY bound antagonists.

Invasion assays

  • Cell invasion assays in response to a chemokine gradient.

  • Initially used SJSA cells.

  • Experiments run in presence and absence of antagonist.


Invasive cxcr4 mutants l.jpg
Invasive CXCR4 mutants bound antagonists.


Slide27 l.jpg

CXCL12 bound antagonists.

Control

Drug/

no CXCL12

Drug + CXCL12


Conclusions l.jpg
CONCLUSIONS bound antagonists.

  • 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.


Acknowledgements l.jpg

Current research group bound antagonists.:

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)

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)


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