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

// 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 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 * These authors contributed equally to the work Correspondence to: John A. Copland, email: // Keywords : stearoyl CoA desaturase, lipid metabolism, high throughput drug screening, cancer, drug discovery Received : June 06, 2017 Accepted : August 16, 2017 Published : October 06, 2017 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 IC 50 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.