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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Coactivator-associated arginine methyltransferase 1 (CARM1) is a validated therapeutic target.
  • Existing CARM1 degraders face translational challenges like poor bioavailability.

Purpose of the Study:

  • To discover novel, drug-like CARM1 degraders.
  • To identify natural products with CARM1-degrading capabilities.

Main Methods:

  • Developed a high-throughput screening platform using HiBiT-tagged CARM1 in MCF7 cells.
  • Screened 1408 plant-derived natural product fractions.
  • Assessed CARM1 degradation and selectivity via luciferase activity.

Main Results:

  • Identified kusunokinin and exostemin as potent CARM1 degraders.
  • These compounds showed selectivity for CARM1 over other methyltransferases.
  • Demonstrated anticancer activity by inhibiting breast cancer cell colony formation and migration.

Conclusions:

  • Kusunokinin and exostemin are promising lead compounds for next-generation CARM1-targeted cancer therapeutics.
  • These natural compounds offer enhanced translational potential compared to existing degraders.