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Discovery of an Efficacious RET PROTAC Degrader with Enhanced Antiproliferative Activity against Resistant Cancer
Qian Zhang1, Yingqi He2,3, Danni Rao4,5
1School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Abstract:
Rearranged during transfection (RET) kinase is a validated therapeutic target for various cancers characterized by RET alterations. Although two selective RET inhibitors, selpercatinib and pralsetinib, have been approved by the FDA, acquired resistance through solvent-front mutations has been identified rapidly. Developing proteolysis targeting chimera (PROTAC) targeting RET mutations offers a promising strategy to combat drug resistance. Herein, we describe the design, synthesis, and evaluation of a series of RET PROTAC degraders. The representative compound QZ2135 (20) effectively degraded RET kinase and its resistant mutants, such as V804M and G810C/R. It also exhibited superior antiproliferative activity against Ba/F3 cells stably expressing oncogenic fusions of RET with solvent-front mutants, including G810C/R/S, compared to its parental inhibitor. Notably, QZ2135 demonstrated in vivo antitumor efficacy in a Ba/F3-KIF5B-RET-G810C xenograft mouse model. Together, this study provides a potential alternative strategy for overcoming acquired resistance to RET inhibitors mediated by solvent-front mutations.
Insights
New proteolysis targeting chimera (PROTAC) compounds effectively degrade rearranged during transfection (RET) kinase and its resistant mutants. This offers a promising strategy to overcome acquired resistance to RET inhibitors in cancer therapy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Rearranged during transfection (RET) kinase is a key therapeutic target in various cancers.
- Approved RET inhibitors face challenges due to rapid acquired resistance, particularly from solvent-front mutations.
- Proteolysis targeting chimera (PROTAC) technology presents a novel approach to overcome drug resistance.
Purpose of the Study:
- To design, synthesize, and evaluate novel RET PROTAC degraders.
- To assess the efficacy of these PROTACs against RET kinase and its resistant mutants.
- To investigate their potential in combating acquired resistance to RET inhibitors.
Main Methods:
- Design and synthesis of a series of RET PROTAC degraders.
- Evaluation of compound efficacy in degrading RET kinase and its mutants (V804M, G810C/R).
- Assessment of antiproliferative activity in Ba/F3 cells with RET fusions and solvent-front mutants.
- In vivo efficacy testing in a xenograft mouse model.
Main Results:
- The representative compound QZ2135 effectively degraded RET kinase and resistant mutants (V804M, G810C/R).
- QZ2135 showed superior antiproliferative activity against cells with RET solvent-front mutants (G810C/R/S) compared to inhibitors.
- QZ2135 demonstrated significant in vivo antitumor efficacy in a relevant mouse model.
Conclusions:
- The developed RET PROTACs, exemplified by QZ2135, are effective in degrading RET kinase and overcoming resistance mutations.
- This PROTAC strategy offers a promising alternative for treating cancers resistant to current RET inhibitors.
- Further development of RET PROTACs could provide a new therapeutic avenue for RET-driven cancers with acquired resistance.
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