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Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of

Lin Du1, Brice A P Wilson1, Ning Li2

  • 1Molecular Targets Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, United States.

Journal of Natural Products
|October 16, 2023
PubMed

Insights

Scientists discovered new natural compounds, aplithianines A and B, from a marine tunicate. Aplithianine A potently inhibits J-PKAcα, a target for fibrolamellar hepatocellular carcinoma (FLHCC), offering a promising lead for cancer drug discovery.

Area of Science:

  • Biochemistry
  • Marine Natural Products Chemistry
  • Oncology

Background:

  • The DNAJB1-PRKACA gene fusion produces J-PKAcα, an active kinase.
  • J-PKAcα is a promising therapeutic target for fibrolamellar hepatocellular carcinoma (FLHCC).
  • Natural products offer a rich source of novel bioactive compounds.

Purpose of the Study:

  • To identify inhibitors of J-PKAcα catalytic activity.
  • To discover novel compounds from natural sources for cancer therapy.
  • To investigate the potential of marine natural products as kinase inhibitors.

Main Methods:

  • High-throughput screening of the NCI Program for Natural Product Discovery (NPNPD) library.
  • Purification and structural elucidation of active compounds from an *Aplidium* sp. marine tunicate.
  • Biochemical assays, including kinome screening and IC50 determination.
  • Cocrystallization and X-ray diffraction for mechanistic studies.
  • Total synthesis of the lead compound.

Main Results:

  • Two novel alkaloids, aplithianines A (1) and B (2), were discovered.
  • Aplithianine A demonstrated potent inhibition of J-PKAcα (IC50 ≈ 1 µM) and wild-type PKA (IC50 = 84 nM).
  • Mechanistic studies revealed competitive binding to the ATP pocket of PKAcα.
  • Aplithianine A exhibited potent inhibition against CLK and PKG family kinases (IC50 ≈ 11-90 nM).
  • An efficient four-step total synthesis of aplithianine A was achieved.

Conclusions:

  • Aplithianines A and B are novel marine alkaloids with significant kinase inhibitory activity.
  • Aplithianine A is a potent inhibitor of J-PKAcα, a key target in FLHCC.
  • The discovery and synthesis of aplithianine A provide a valuable tool for further research into kinase-targeted cancer therapies.

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