The Discovery of MMP7 Inhibitors Exploiting a Novel Selectivity Trigger
Corresponding Author
Dr. Karl Edman
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700Search for more papers by this authorDr. Mark Furber
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorPaul Hemsley
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorCristian Johansson
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700
Search for more papers by this authorDr. Garry Pairaudeau
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorDr. Jens Petersen
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700
Search for more papers by this authorDr. Michael Stocks
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorDr. Anu Tervo
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700
Search for more papers by this authorDr. Alison Ward
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorDr. Edward Wells
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorLisa Wissler
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700
Search for more papers by this authorCorresponding Author
Dr. Karl Edman
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700Search for more papers by this authorDr. Mark Furber
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorPaul Hemsley
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorCristian Johansson
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700
Search for more papers by this authorDr. Garry Pairaudeau
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorDr. Jens Petersen
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700
Search for more papers by this authorDr. Michael Stocks
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorDr. Anu Tervo
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700
Search for more papers by this authorDr. Alison Ward
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorDr. Edward Wells
Departments of Medicinal Chemistry and BioSciences, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH (UK)
Search for more papers by this authorLisa Wissler
Global Structural Chemistry, AstraZeneca Mölndal, Pepparedsleden 1, 43183 Mölndal (Sweden), Fax: (+46) 31-776-3700
Search for more papers by this authorGraphical Abstract
Trigger happy! High-throughput screening was used to identify selective MMP7 inhibitors. Subsequent analysis by X-ray crystallography revealed the underlying features for the selectivity trigger, unique to MMP7. In addition, further structural studies increased the understanding of the plasticity of the MMP7 active site. Finally, a single round of chemistry resulted in compounds with improved potency and retained selectivity.
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References
- 1L. J. McCawley, L. M. Matrisian, Curr. Opin. Cell Biol. 2001, 13, 534–540.
- 2B. Wielockx, C. Libert, C. Wilson, Cytokine Growth Factor Rev. 2004, 15, 111–115.
- 3Y. Fujita, T. Shiomi, S. Yanagimoto, H. Matsumoto, Y. Toyama, Y. Okada, Arthritis Rheum. 2006, 54, 3233–3243.
- 4B. Fingleton, Curr. Pharm. Des. 2007, 13, 333–346.
- 5G. Dormán, S. Cseh, I. Hajdu, L. Barna, D. Konya, K. Kupai, L. Kovacs, P. Ferdinandy, Drugs 2010, 70, 949–964.
- 6J. F. Fisher, S. Mobashery, Cancer Metastasis Rev. 2006, 25, 115–136.
- 7Sulfonamide carboxylic acids have been described as inhibitors of other MMPs for example, C. T. Supuran, A. Scozzafava, Eur. J. Pharm. Sci. 2000, 10, 67–76.
- 8M. F. Browner, W. W. Smith, A. L. Castelhano, Biochemistry 1995, 34, 6602–6610.
- 9K. Maskos, Biochimie 2005, 87, 249–263.
- 10B. Lovejoy, A. R. Welch, S. Carr, C. Luong, C. Broka, R. T. Hendricks, J. A. Campbell, K. A. M. Walker, R. Martin, H. Van Wart, M. F. Browner, Nat. Struct. Biol. 1999, 6, 217–221.
- 11L. Aureli, M. Gioia, I. Cerbara, S. Monaco, G. F. Fasciglione, S. Marini, P. Ascenzi, A. Topai, M. Coletta, Curr. Med. Chem. 2008, 15, 2192–2222.
- 12C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, Adv. Drug Delivery Rev. 1997, 23, 3–25.
- 13Collaborative Computational Project, Number 4, Acta Crystallogr., Sect. D: Biol. Crystallogr. 1994, 50, 760–763.
- 14P. Emsley, K. Cowtan, Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60, 2126–2132.
