Oncotarget

Priority Research Papers:

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

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 and John A. Copland _

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Oncotarget. 2018; 9:3-20. https://doi.org/10.18632/oncotarget.21545

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Abstract

Christina A. von Roemeling1,*, Thomas R. Caulfield2,*, Laura Marlow3, Ilah Bok3, Jiang Wen4, James L. Miller3, Robert Hughes5, Lori Hazlehurst6, Anthony B. Pinkerton7, Derek C. Radisky3, Han W. Tun3,8, Yon Son Betty Kim2,3,9, Amy L. Lane5, John A. Copland3

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 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.


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