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A Dual-Target and Dual-Mechanism Design Strategy by Combining Inhibition and Degradation Together
Yongbo Liu1, Xiuyun Sun2, Qianlong Liu1
1MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, State Key Laboratory of Molecular Oncology, Tsinghua University, Beijing 100084, China.
Abstract:
Glioblastoma, a highly aggressive brain tumor, lacks effective treatment with low 5 year survival rates. Urgency for new therapies is evident. Mammalian targets of rapamycin (mTOR) and G1 to S phase transition 1 gene (GSPT1) are overexpressed in glioblastoma, regulating vital cellular functions. Current mTOR inhibitors face challenges in clinical efficacy and drug resistance. Similarly, GSPT1-targeting therapies have not progressed of glioblastoma in clinical trials. Research studies suggested that combining mTOR inhibition with GSPT1 degradation may overcome resistance and enhance efficacy. We propose the concept of jointly implementing inhibition and degradation on different proteins, integrating the properties of inhibitors and degraders into the same molecule. Introducing YB-3-17, a novel bifunctional molecule, robustly inhibits mTOR and selectively degrades GSPT1. As a tool compound for proof-of-concept studies, YB-3-17 sharpens selectivity, avoiding off-target effects, and selectively induces GSPT1 degradation and mTOR inhibition, showing superior efficacy in tumor cell lines compared to that of standalone therapies. RNA-seq analysis highlights the advantages of YB-3-17 over mTOR inhibitor treatment. YB-3-17 can safely and effectively inhibit tumor growth in mice, offering a promising direction for precision treatment of glioblastoma, representing the first attempt to combine mTOR inhibition with GSPT1 degradation. This work also demonstrates that it is conceptually possible to successfully combine the properties of small molecule inhibitors and degraders into a single molecule, killing two birds with one stone.
Insights
A new bifunctional molecule, YB-3-17, simultaneously inhibits mTOR and degrades GSPT1, offering a promising precision therapy for glioblastoma. This approach overcomes resistance and enhances efficacy in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Glioblastoma is an aggressive brain tumor with poor survival rates, necessitating novel therapeutic strategies.
- Mammalian targets of rapamycin (mTOR) and G1 to S phase transition 1 gene (GSPT1) are overexpressed in glioblastoma, contributing to tumor growth.
- Existing mTOR inhibitors and GSPT1-targeting therapies show limited clinical success due to resistance and efficacy challenges.
Purpose of the Study:
- To develop a novel bifunctional molecule combining mTOR inhibition and GSPT1 degradation for glioblastoma treatment.
- To evaluate the efficacy and safety of the bifunctional molecule YB-3-17 in preclinical glioblastoma models.
- To demonstrate the feasibility of integrating inhibitor and degrader properties into a single molecule.
Main Methods:
- Design and synthesis of YB-3-17, a novel bifunctional molecule targeting both mTOR and GSPT1.
- In vitro assessment of YB-3-17's efficacy in glioblastoma cell lines, comparing it to standalone therapies.
- RNA-sequencing analysis to elucidate molecular mechanisms of YB-3-17.
- In vivo studies in mice to evaluate tumor growth inhibition and safety.
Main Results:
- YB-3-17 robustly inhibits mTOR and selectively degrades GSPT1, demonstrating superior efficacy over standalone treatments in glioblastoma cell lines.
- RNA-seq analysis revealed distinct advantages of YB-3-17 compared to mTOR inhibitor treatment alone.
- YB-3-17 demonstrated safe and effective inhibition of glioblastoma tumor growth in preclinical mouse models.
Conclusions:
- YB-3-17 represents a first-in-class bifunctional molecule combining mTOR inhibition and GSPT1 degradation for glioblastoma.
- This dual-action approach offers enhanced efficacy and overcomes resistance mechanisms in glioblastoma.
- The successful integration of inhibitor and degrader functionalities into a single molecule opens new avenues for precision cancer therapy.
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