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Targeting Oncogenic RET Kinase by Simultaneously Inhibiting Kinase Activity and Degrading the Protein.

Yafeng Wang1, Xueqing Hu2, Shriya Pandey2

  • 1Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States.

Journal of Medicinal Chemistry
|December 26, 2024
PubMed
Summary
This summary is machine-generated.

A novel PROTAC degrader, YW-N-7, simultaneously inhibits and depletes oncogenic RET protein, offering a new strategy for RET-altered cancers. This dual action enhances anti-cancer efficacy, even potentiating existing therapies.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The rearranged-during-transfection (RET) kinase is a key target in RET-altered cancers.
  • Approved RET inhibitors like selpercatinib can increase oncogenic RET protein levels, potentially limiting efficacy.
  • A need exists for therapies that simultaneously inhibit and reduce oncogenic RET protein levels.

Purpose of the Study:

  • To develop proteolysis targeting chimera (PROTAC) degraders for oncogenic RET protein.
  • To investigate a novel compound, YW-N-7, for its dual action on RET kinase.
  • To evaluate the therapeutic potential of simultaneously inhibiting and degrading RET in cancer models.

Main Methods:

  • Development of PROTAC degraders targeting oncogenic RET.
  • In vitro and in vivo evaluation of compound YW-N-7.
  • Proteomic analysis to assess specificity.
  • Assessment of YW-N-7 in combination with LOXO-292 in cell cultures.
  • Testing in KIF5B-RET-driven xenograft tumor models.

Main Results:

  • Compound YW-N-7 demonstrated dual action, selectively inhibiting and depleting RET protein.
  • Proteomic analysis confirmed high specificity of YW-N-7 for RET.
  • Reducing RET fusion protein with YW-N-7 potentiated the activity of selpercatinib (LOXO-292).
  • YW-N-7 showed significant efficacy in inhibiting KIF5B-RET-driven xenograft tumors in vivo.

Conclusions:

  • YW-N-7 is a novel PROTAC degrader with dual inhibitory and depleting activity against oncogenic RET.
  • Simultaneous inhibition and degradation of RET kinase is a feasible therapeutic strategy for RET-altered cancers.
  • YW-N-7 holds promise for improving cancer treatment by overcoming limitations of current RET inhibitors.