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Murray CW, Berdini V, Buck IM, et al. Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors. ACS Med Chem Lett. 2015;6(7):798-803doi: 10.1021/acsmedchemlett.5b00143.
Murray, C. W., Berdini, V., Buck, I. M., Carr, M. E., Cleasby, A., Coyle, J. E., Curry, J. E., Day, J. E., Day, P. J., Hearn, K., Iqbal, A., Lee, L. Y., Martins, V., Mortenson, P. N., Munck, J. M., Page, L. W., Patel, S., Roomans, S., Smith, K., Tamanini, E., & Saxty, G. (2015). Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors. ACS medicinal chemistry letters, 6(7), 798-803. https://doi.org/10.1021/acsmedchemlett.5b00143
Murray, Christopher W, et al. "Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors." ACS medicinal chemistry letters vol. 6,7 (2015): 798-803. doi: https://doi.org/10.1021/acsmedchemlett.5b00143
Murray CW, Berdini V, Buck IM, Carr ME, Cleasby A, Coyle JE, Curry JE, Day JE, Day PJ, Hearn K, Iqbal A, Lee LY, Martins V, Mortenson PN, Munck JM, Page LW, Patel S, Roomans S, Smith K, Tamanini E, Saxty G. Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors. ACS Med Chem Lett. 2015 Jun 04;6(7):798-803. doi: 10.1021/acsmedchemlett.5b00143. eCollection 2015 Jul 09. PMID: 26191369; PMCID: PMC4499826.
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ACS Med Chem Lett. 2015 Jun 04;6(7):798-803. doi: 10.1021/acsmedchemlett.5b00143. eCollection 2015 Jul 09.

Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.

ACS medicinal chemistry letters

Christopher W Murray, Valerio Berdini, Ildiko M Buck, Maria E Carr, Anne Cleasby, Joseph E Coyle, Jayne E Curry, James E H Day, Phillip J Day, Keisha Hearn, Aman Iqbal, Lydia Y W Lee, Vanessa Martins, Paul N Mortenson, Joanne M Munck, Lee W Page, Sahil Patel, Susan Roomans, Kirsten Smith, Emiliano Tamanini, Gordon Saxty

Affiliations

  1. Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.

PMID: 26191369 PMCID: PMC4499826 DOI: 10.1021/acsmedchemlett.5b00143

Abstract

The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the "back-to-front" design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines.

Keywords: back to front kinase design; discoidin domain receptor; fragment-based drug design

References

  1. Cancer Discov. 2011 Jun;1(1):78-89 - PubMed
  2. Bioorg Med Chem Lett. 2008 Oct 1;18(19):5285-9 - PubMed
  3. J Med Chem. 2014 May 22;57(10 ):4252-62 - PubMed
  4. J Med Chem. 2004 May 20;47(11):2768-75 - PubMed
  5. Annu Rev Cell Dev Biol. 2011;27:265-90 - PubMed
  6. Drug Discov Today. 2004 May 15;9(10):430-1 - PubMed
  7. Bioorg Med Chem Lett. 2013 May 15;23(10):2962-7 - PubMed
  8. Cancer Res. 2014 Dec 15;74(24):7217-28 - PubMed
  9. J Med Chem. 2006 Nov 16;49(23):6819-32 - PubMed
  10. Biochem J. 2013 Sep 15;454(3):501-13 - PubMed
  11. Mol Cell. 1997 Dec;1(1):25-34 - PubMed
  12. Cell Signal. 2006 Aug;18(8):1108-16 - PubMed
  13. Nat Cell Biol. 2013 Jun;15(6):677-87 - PubMed
  14. Cancer Metastasis Rev. 2012 Jun;31(1-2):295-321 - PubMed
  15. J Med Chem. 2008 Aug 28;51(16):4986-99 - PubMed
  16. J Med Chem. 2011 Jul 28;54(14):5131-43 - PubMed
  17. Mol Cancer Ther. 2011 Sep;10(9):1542-52 - PubMed
  18. J Med Chem. 2007 Sep 6;50(18):4351-73 - PubMed
  19. J Med Chem. 2015 Apr 23;58(8):3287-301 - PubMed
  20. J Med Chem. 2009 Jan 22;52(2):379-88 - PubMed
  21. J Med Chem. 2007 May 17;50(10):2293-6 - PubMed
  22. Mol Cancer Ther. 2014 Feb;13(2):475-82 - PubMed
  23. ACS Chem Biol. 2013 Oct 18;8(10 ):2145-50 - PubMed
  24. ACS Med Chem Lett. 2012 Feb 28;3(4):342-6 - PubMed
  25. Nat Chem Biol. 2006 Jul;2(7):358-64 - PubMed
  26. J Med Chem. 2002 Jul 4;45(14):2994-3008 - PubMed
  27. ACS Med Chem Lett. 2014 May 23;6(1):25-30 - PubMed
  28. J Mol Biol. 2014 Jun 26;426(13):2457-70 - PubMed
  29. J Thorac Oncol. 2014 Jun;9(6):900-4 - PubMed
  30. J Med Chem. 2013 Apr 25;56(8):3281-95 - PubMed
  31. J Med Chem. 2005 Jan 27;48(2):414-26 - PubMed

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