Display options
Cite
Niwa T, Asaki T, Kimura S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Anal Chem Insights. 2007;2:93-106
Niwa, T., Asaki, T., & Kimura, S. (2007). NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Analytical chemistry insights, 293-106.
Niwa, Tomoko, et al. "NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor." Analytical chemistry insights vol. 2 (2007): 93-106.
Niwa T, Asaki T, Kimura S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Anal Chem Insights. 2007 Nov 14;2:93-106. PMID: 19662183; PMCID: PMC2716809.
Copy Download .nbib Format: NLM
Share it on

Anal Chem Insights. 2007 Nov 14;2:93-106.

NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor.

Analytical chemistry insights

Tomoko Niwa, Tetsuo Asaki, Shinya Kimura

Affiliations

  1. Discovery Research Laboratories, Nippon Shinyaku Co., Ltd. 14, Nishinosho-Monguchi-Cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan.

PMID: 19662183 PMCID: PMC2716809

Abstract

Protein kinases catalyze the transfer of the gamma-phosphoryl group of adenosine triphosphate (ATP) to the hydroxyl groups of protein side chains, and they play critical roles in regulating cellular signal transduction and other biochemical processes. They are attractive targets for today's drug discovery and development, and many pharmaceutical companies are intensively developing various kinds of protein kinase inhibitors. A good example is the recent success with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (Gleevec) in the treatment of chronic myeloid leukemia. Though imatinib has dramatically improved the treatment of Bcr-Abl-positive chronic myeloid leukemia, resistance is often found in patients with advanced-stage disease. Several mechanisms have been proposed to explain this resistance, including point mutations within the Abl kinase domain, amplification of the bcr-abl gene, overexpression of the corresponding mRNA, increased drug efflux mediated by P-glycoprotein, and activation of the Src-family kinase (SFK) Lyn. We set out to develop a novel drug whose affinity for Abl is higher than that of imatinib and whose specificity in inhibiting Lyn is higher than that of SFK/Abl inhibitors such as dasatinib (Sprycel) or bosutinib (SKI-606). Our work has led to the development of NS-187 (INNO-406), a novel Abl/Lyn dual tyrosine kinase inhibitor with clinical prospects. To provide an overview of how a selective kinase inhibitor has been developed, this review presents chemical-modification studies carried out with the guidance of molecular modeling, the structural basis for the high potency and selectivity of NS-187 based on the X-ray structure of the NS-187/Abl complex, and the biological profiling of NS-187, including site-directed mutagenesis experiments.

Keywords: Bcr-Abl; INNO-406; Lyn; NS-187; chronic myeloid leukemia; imatinib

References

  1. Blood. 2007 Jan 1;109(1):306-14 - PubMed
  2. Curr Opin Hematol. 2004 Jan;11(1):35-43 - PubMed
  3. J Chem Inf Model. 2006 Sep-Oct;46(5):2158-66 - PubMed
  4. Am J Physiol Heart Circ Physiol. 2003 Apr;284(4):H1449-53 - PubMed
  5. Cancer Res. 1996 Jan 1;56(1):100-4 - PubMed
  6. Nat Rev Drug Discov. 2002 Apr;1(4):309-15 - PubMed
  7. N Engl J Med. 2001 Apr 5;344(14):1038-42 - PubMed
  8. Cell Death Differ. 2007 Sep;14(9):1667-77 - PubMed
  9. Leukemia. 2004 Aug;18(8):1321-31 - PubMed
  10. Leuk Res. 2006 Nov;30(11):1443-6 - PubMed
  11. Blood. 2004 Oct 15;104(8):2532-9 - PubMed
  12. Science. 2002 Dec 6;298(5600):1912-34 - PubMed
  13. Science. 2001 Aug 3;293(5531):876-80 - PubMed
  14. Nature. 1996 Oct 10;383(6600):528-31 - PubMed
  15. Blood. 2005 Dec 1;106(12):3948-54 - PubMed
  16. Science. 2004 Jul 16;305(5682):399-401 - PubMed
  17. Blood. 2004 Apr 15;103(8):2873-8 - PubMed
  18. Bioorg Med Chem Lett. 2007 May 15;17(10):2712-7 - PubMed
  19. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1421-5 - PubMed
  20. Science. 1988 Jul 1;241(4861):42-52 - PubMed
  21. Blood. 2003 Jan 15;101(2):690-8 - PubMed
  22. Cancer Cell. 2005 Feb;7(2):129-41 - PubMed
  23. J Hypertens. 2001 Mar;19(3):441-9 - PubMed
  24. Blood. 2005 Apr 1;105(7):2640-53 - PubMed
  25. N Engl J Med. 2003 Oct 9;349(15):1451-64 - PubMed
  26. Cancer Res. 2002 Aug 1;62(15):4244-55 - PubMed
  27. Mol Cell Biol. 2002 Apr;22(8):2427-40 - PubMed
  28. Cancer Res. 2003 Jan 15;63(2):375-81 - PubMed
  29. Blood. 2002 Mar 1;99(5):1860-2 - PubMed
  30. Blood. 2003 Jul 1;102(1):83-6 - PubMed
  31. N Engl J Med. 2003 Mar 13;348(11):994-1004 - PubMed
  32. Cancer Res. 2002 Aug 1;62(15):4236-43 - PubMed
  33. Cancer. 2003 Sep 1;98(5):888-93 - PubMed
  34. Biochim Biophys Acta. 2002 Jul 18;1587(2-3):318-25 - PubMed
  35. J Biol Chem. 2004 Aug 13;279(33):34227-39 - PubMed
  36. Nat Med. 2004 Nov;10(11):1187-9 - PubMed
  37. Methods Enzymol. 1991;200:38-62 - PubMed
  38. N Engl J Med. 1999 Apr 29;340(17):1330-40 - PubMed
  39. Blood. 2002 Sep 15;100(6):1965-71 - PubMed

Publication Types