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

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.