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von Roemeling CA, Caulfield TR, Marlow L, et al. Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy. Oncotarget. 2017;9(1):3-20doi: 10.18632/oncotarget.21545.
von Roemeling, C. A., Caulfield, T. R., Marlow, L., Bok, I., Wen, J., Miller, J. L., Hughes, R., Hazlehurst, L., Pinkerton, A. B., Radisky, D. C., Tun, H. W., Kim, Y. S. B., Lane, A. L., & Copland, J. A. (2018). Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy. Oncotarget, 9(1), 3-20. https://doi.org/10.18632/oncotarget.21545
von Roemeling, Christina A, et al. "Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy." Oncotarget vol. 9,1 (2018): 3-20. doi: https://doi.org/10.18632/oncotarget.21545
von Roemeling CA, Caulfield TR, Marlow L, Bok I, Wen J, Miller JL, Hughes R, Hazlehurst L, Pinkerton AB, Radisky DC, Tun HW, Kim YSB, Lane AL, Copland JA. Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy. Oncotarget. 2017 Oct 06;9(1):3-20. doi: 10.18632/oncotarget.21545. eCollection 2018 Jan 02. PMID: 29416592; PMCID: PMC5787466.
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Oncotarget. 2017 Oct 06;9(1):3-20. doi: 10.18632/oncotarget.21545. eCollection 2018 Jan 02.

Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy.

Oncotarget

Christina A von Roemeling, Thomas R Caulfield, Laura Marlow, Ilah Bok, Jiang Wen, James L Miller, Robert Hughes, Lori Hazlehurst, Anthony B Pinkerton, Derek C Radisky, Han W Tun, Yon Son Betty Kim, Amy L Lane, John A Copland

Affiliations

  1. The Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA.
  2. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  3. Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
  4. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  5. Department of Chemistry, University of North Florida, Jacksonville, FL, USA.
  6. Modulation Therapeutics, Inc. Morgantown WV, USA.
  7. Conrad Prebys Center for Chemical Genomics, Sanford Burnham Medical Discovery Institute, La Jolla, CA, USA.
  8. Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA.
  9. Department of Neurosurgery, Mayo Clinic, Jacksonville, FL, USA.

PMID: 29416592 PMCID: PMC5787466 DOI: 10.18632/oncotarget.21545

Abstract

Here we present an innovative computational-based drug discovery strategy, coupled with machine-based learning and functional assessment, for the rational design of novel small molecule inhibitors of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1). Our methods resulted in the discovery of several unique molecules, of which our lead compound SSI-4 demonstrates potent anti-tumor activity, with an excellent pharmacokinetic and toxicology profile. We improve upon key characteristics, including chemoinformatics and absorption/distribution/metabolism/excretion (ADME) toxicity, while driving the IC50 to 0.6 nM in some instances. This approach to drug design can be executed in smaller research settings, applied to a wealth of other targets, and paves a path forward for bringing small-batch based drug programs into the Clinic.

Keywords: cancer; drug discovery; high throughput drug screening; lipid metabolism; stearoyl CoA desaturase

Conflict of interest statement

CONFLICTS OF INTEREST There is no conflict of interest.

References

  1. Bioorg Med Chem Lett. 2012 Apr 1;22(7):2444-9 - PubMed
  2. J Comput Aided Mol Des. 2006 Oct-Nov;20(10-11):647-71 - PubMed
  3. J Chem Inf Model. 2006 Jul-Aug;46(4):1535 - PubMed
  4. J Clin Endocrinol Metab. 2015 May;100(5):E697-709 - PubMed
  5. Mol Cancer Res. 2011 Nov;9(11):1551-61 - PubMed
  6. Carcinogenesis. 2010 Sep;31(9):1509-15 - PubMed
  7. Eur J Pharmacol. 2013 May 5;707(1-3):140-6 - PubMed
  8. J Chem Inf Model. 2009 Oct;49(10):2356-68 - PubMed
  9. Science. 2004 Mar 19;303(5665):1813-8 - PubMed
  10. J Biol Chem. 2016 Dec 16;291(51):26304-26319 - PubMed
  11. Drug Discov Today. 2012 Apr;17(7-8):310-24 - PubMed
  12. J Med Chem. 2007 Jun 28;50(13):3086-100 - PubMed
  13. J Chem Inf Model. 2013 Jan 28;53(1):56-65 - PubMed
  14. Dis Model Mech. 2013 Nov;6(6):1353-63 - PubMed
  15. Nat Rev Cancer. 2016 Nov;16(11):732-749 - PubMed
  16. J Med Chem. 2011 Jul 28;54(14 ):5082-96 - PubMed
  17. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4151-8 - PubMed
  18. Proteins. 2012 Nov;80(11):2489-500 - PubMed
  19. BMC Bioinformatics. 2011 Dec 15;12:474 - PubMed
  20. Biochim Biophys Acta. 2016 Dec;1861(12 Pt A):1865-1880 - PubMed
  21. Nat Cell Biol. 2015 Apr;17(4):351-9 - PubMed
  22. Nature. 2013 Jul 4;499(7456):43-9 - PubMed
  23. Sci Signal. 2013 Apr 02;6(269):pl1 - PubMed
  24. Eur J Med Chem. 2011 May;46(5):1892-6 - PubMed
  25. J Chem Inf Model. 2007 May-Jun;47(3):1067-86 - PubMed
  26. Chem Biol Drug Des. 2015 Nov;86(5):1036-48 - PubMed
  27. PLoS One. 2013 Dec 18;8(12):e82241 - PubMed
  28. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4298-302 - PubMed
  29. Bioorg Med Chem Lett. 2010 Jan 15;20(2):499-502 - PubMed
  30. Eur J Med Chem. 2011 Aug;46(8):3499-508 - PubMed
  31. Curr Pharm Des. 2003;9(20):1649-64 - PubMed
  32. Pharmacol Rev. 2013 Dec 31;66(1):334-95 - PubMed
  33. Clin Cancer Res. 2013 May 1;19(9):2368-80 - PubMed
  34. Oncotarget. 2016 Aug 2;7(31):49322-49333 - PubMed
  35. J Chem Inf Model. 2010 Jun 28;50(6):1165-72 - PubMed
  36. Anal Chem. 2005 May 1;77(9):2889-94 - PubMed
  37. Brain. 2017 Jan;140(1):98-117 - PubMed
  38. Nat Chem Biol. 2016 Apr;12 (4):218-25 - PubMed
  39. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6366-9 - PubMed
  40. Anal Chim Acta. 2008 Oct 3;627(1):105-11 - PubMed
  41. Chem Biol. 2004 Feb;11(2):149-51 - PubMed
  42. Endocr Relat Cancer. 2012 Apr 10;19(2):197-208 - PubMed
  43. PLoS Comput Biol. 2014 Nov 06;10 (11):e1003935 - PubMed
  44. J Mol Biol. 2001 Aug 17;311(3):445-52 - PubMed
  45. Chem Biol Drug Des. 2006 May;67(5):370-2 - PubMed
  46. J Biomol Screen. 2011 Jun;16(5):506-17 - PubMed
  47. Drug Discov Today Technol. 2004 Dec;1(3):217-24 - PubMed
  48. Oncogene. 2006 Apr 13;25(16):2304-17 - PubMed
  49. J Chem Inf Model. 2007 May-Jun;47(3):1097-110 - PubMed
  50. Oncogenesis. 2016 Jan 25;5:e189 - PubMed
  51. J Biol Chem. 2000 Sep 1;275(35):27013-20 - PubMed

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