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Discovery of Fatty Acids as Specific Shp2 Inhibitors with Anticancer Properties

Strategic Insights

— 1 min read

D.P. Liu and colleagues at the University of California have made a significant breakthrough in cancer therapy research by identifying fatty acids as specific inhibitors of the proto-oncogenic protein Shp2. Through a bioguided isolation process, the researchers isolated 13 compounds from the root of Angelica dahurica, including 10 fatty acids and derivatives, which showed considerable inhibitory effects on Shp2 activity. Notably, one compound, 14Z, 17Z-tricosadienoic acid (5), a polyunsaturated fatty acid, demonstrated strong anticancer properties by inducing poly (ADP-ribose) polymerase (PARP) cleavage and increasing caspase activity in HepG2 cells.

Key Takeaways:

  • The study identified 2000 plant extracts, with the ethyl acetate (EtOAc) extract of the root of Angelica dahurica showing considerable inhibitory effects on Shp2 activity (IC50 = 21.6 mg/L).
  • Bioguided isolation led to the identification of 13 compounds, including 10 fatty acids and derivatives, which were isolated from the plant for the first time.
  • 8Z, 11Z-Feptadecadienoic acid (4), 14Z, 17Z-tricosadienoic acid (5), caffeic acid (9), and 2-hydroxy-3-[(1-oxododecyl) oxy]propyl-beta-D-glucopyranoside (11) showed considerable selective inhibition of Shp2 activity.
  • Compound 5, a polyunsaturated fatty acid, strongly induced poly (ADP-ribose) polymerase (PARP) cleavage and increased the activities of caspase-3, caspase-8, and caspase-9 at 100 mcM.
  • Compound 5 also inhibited colony formation of HepG2 cells in a dose-dependent manner.
  • The study provided the molecular basis for one active compound as a novel potential anticancer drug.

Statistics:

  • 2000 plant extracts were screened for natural specific inhibitors of Shp2.
  • 13 compounds were isolated from the root of Angelica dahurica, including 10 fatty acids and derivatives.
  • The IC50 value for Shp2 activity inhibition was 21.6 mg/L.
  • Compound 5 at 100 mcM induced poly (ADP-ribose) polymerase (PARP) cleavage in a dose- and time-dependent manner.
  • Compound 5 increased the activities of caspase-3, caspase-8, and caspase-9 at 100 mcM.

Sources:

  • Liu, D.P. et al. (2011). Fatty acids as natural specific inhibitors of the proto-oncogenic protein Shp2. Bioorganic & Medicinal Chemistry Letters, 21(22), 6833-6837.
  • University of California, Molecular Pathology Graduate Program, La Jolla, CA 92093, United States.
  • Pergamon-Elsevier Science Ltd, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, England.

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