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Proteolysis Targeting Chimera Degraders of the METTL3-14 m6A-RNA Methyltransferase

Francesco Errani1, Annalisa Invernizzi1, Marcin Herok1

  • 1Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland.

JACS Au
|March 1, 2024
PubMed

Insights

Researchers developed novel PROTACs targeting METTL3-14, crucial for cancer. These molecules effectively degrade METTL3 and METTL14 proteins in leukemia and prostate cancer cells, offering new therapeutic avenues.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Chemical Biology

Background:

  • N6-methyladenosine (m6A) is the most prevalent RNA modification, regulated by the METTL3-14 complex.
  • The METTL3-14 complex is implicated in the pathogenesis of acute myeloid leukemia (AML) and other cancers.

Purpose of the Study:

  • To develop the first proteolysis targeting chimeras (PROTACs) targeting the METTL3-14 complex.
  • To investigate the efficacy of novel PROTACs in degrading METTL3 and METTL14 proteins in cancer cell lines.

Main Methods:

  • PROTAC design utilizing the crystal structure of METTL3-14 complexed with UZH2 inhibitor.
  • Synthesis and optimization of PROTACs with varying alkyl linkers.
  • Validation of ternary complex formation via FRET and in vitro ubiquitination assays.
  • Assessment of protein degradation by Western blot in MOLM-13, other AML, and PC3 cell lines.

Main Results:

  • Developed 26 PROTACs based on UZH2 and alkyl linkers.
  • Identified PROTACs 14, 20, 22, 24, and 30 demonstrating significant METTL3/METTL14 degradation (>50%).
  • Observed substantial protein degradation in multiple AML cell lines and the PC3 prostate cancer cell line.

Conclusions:

  • Successfully designed and synthesized the first PROTACs targeting the epitranscriptomic protein METTL3-14.
  • Demonstrated potent degradation of METTL3 and/or METTL14 in various cancer cell lines, highlighting therapeutic potential.
  • Established a foundation for developing targeted cancer therapies based on METTL3-14 degradation.

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