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, John A. 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
Externally publishedYes

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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 R.; Marlow, Laura; Bok, Ilah; Wen, Jiang; Miller, James L.; Hughes, Robert; Hazlehurst, Lori; Pinkerton, Anthony B.; Radisky, Derek C.; Tun, Han W.; Kim, Yon Son Betty; Lane, Amy L.; Copland, John A.

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

Research output: Contribution to journalArticle

von Roemeling, CA, Caulfield, TR, Marlow, L, Bok, I, Wen, J, Miller, JL, Hughes, R, Hazlehurst, L, Pinkerton, AB, Radisky, DC, Tun, HW, Kim, YSB, Lane, AL & Copland, JA 2018, 'Accelerated bottom-up drug design platform enables the discovery of novel stearoyl-CoA desaturase 1 inhibitors for cancer therapy', Oncotarget, vol. 9, no. 1, pp. 3-20. https://doi.org/10.18632/oncotarget.21545
von Roemeling, Christina A. ; Caulfield, Thomas R. ; Marlow, Laura ; Bok, Ilah ; Wen, Jiang ; Miller, James L. ; Hughes, Robert ; Hazlehurst, Lori ; Pinkerton, Anthony B. ; Radisky, Derek C. ; Tun, Han W. ; Kim, Yon Son Betty ; Lane, Amy L. ; Copland, John A. / 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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