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

  • Oncotarget. 2017 Oct 6;9(1):3-20. doi: 10.18632/oncotarget.21545.
Christina A von Roemeling  1 ,  Thomas R Caulfield  2 ,  Laura Marlow  3 ,  Ilah Bok  3 ,  Jiang Wen  4 ,  James L Miller  3 ,  Robert Hughes  5 ,  Lori Hazlehurst  6 ,  Anthony B Pinkerton  7 ,  Derek C Radisky  3 ,  Han W Tun  3  8 ,  Yon Son Betty Kim  2  3  9 ,  Amy L Lane  5 ,  John A Copland  3
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 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.
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