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

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3-20
Number of pages18
JournalOncotarget
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2018

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Stearoyl-CoA Desaturase
Drug Design
Enzyme Inhibitors
Drug Discovery
Toxicology
Inhibitory Concentration 50
Pharmacokinetics
Research
Pharmaceutical Preparations
Neoplasms
Therapeutics
Lead
Machine Learning

Keywords

  • Cancer
  • Drug discovery
  • High throughput drug screening
  • Lipid metabolism
  • Stearoyl CoA desaturase

ASJC Scopus subject areas

  • Oncology

Cite this

Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy. / von Roemeling, Christina A.; Caulfield, Thomas; Marlow, Laura; Bok, Ilah; Wen, Jiang; Miller, James L.; Hughes, Robert; Hazlehurst, Lori; Pinkerton, Anthony B.; Radisky, Derek C; Tun, Han W; Kim, Y S Betty; Lane, Amy L.; Copland, John A III.

In: Oncotarget, Vol. 9, No. 1, 01.01.2018, p. 3-20.

Research output: Contribution to journalArticle

von Roemeling, Christina A. ; Caulfield, Thomas ; Marlow, Laura ; Bok, Ilah ; Wen, Jiang ; Miller, James L. ; Hughes, Robert ; Hazlehurst, Lori ; Pinkerton, Anthony B. ; Radisky, Derek C ; Tun, Han W ; Kim, Y S Betty ; Lane, Amy L. ; Copland, John A III. / Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy. In: Oncotarget. 2018 ; Vol. 9, No. 1. pp. 3-20.
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