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

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

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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