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Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer
Lin Ma1, Yingying Li1, Ruixiang Luo1
1Affiliated Yongkang First People's Hospital and School of Pharmacy, Hangzhou Medical College, Hangzhou 310012 Zhejiang, China.
Abstract:
Abnormal activation of fibroblast growth factor receptors (FGFRs) results in the development and progression of human cancers. FGFR2 is frequently amplified or mutated in cancers; therefore, it is an attractive target for tumor therapy. Despite the development of several pan-FGFR inhibitors, their long-term therapeutic efficacy is hindered by acquired mutations and low isoform selectivity. Herein, we report the discovery of an efficient and selective FGFR2 proteolysis-targeting chimeric molecule, LC-MB12, that incorporates an essential rigid linker. LC-MB12 preferentially internalizes and degrades membrane-bound FGFR2 among the four FGFR isoforms; this may promote greater clinical benefits. LC-MB12 exhibits superior potency in FGFR signaling suppression and anti-proliferative activity compared to the parental inhibitor. Furthermore, LC-MB12 is orally bioavailable and shows significant antitumor effects in FGFR2-dependent gastric cancer in vivo. Taken together, LC-MB12 is a candidate FGFR2 degrader for alternative FGFR2-targeting strategies and offers a promising starting point for drug development.
Insights
A novel molecule, LC-MB12, selectively degrades fibroblast growth factor receptor 2 (FGFR2), offering a promising new strategy for treating FGFR2-driven cancers with improved efficacy and reduced resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Abnormal fibroblast growth factor receptor (FGFR) signaling drives cancer development and progression.
- FGFR2 is a key oncogenic driver in various human cancers, making it a therapeutic target.
- Existing pan-FGFR inhibitors face challenges like acquired resistance and lack of isoform selectivity.
Purpose of the Study:
- To discover and characterize a novel, selective FGFR2 degrader.
- To evaluate the efficacy of the new molecule in preclinical cancer models.
Main Methods:
- Design and synthesis of a proteolysis-targeting chimeric molecule (LC-MB12) with a rigid linker.
- In vitro assessment of FGFR2 degradation, signaling inhibition, and anti-proliferative activity.
- In vivo evaluation of antitumor efficacy in gastric cancer models.
Main Results:
- LC-MB12 efficiently and selectively degrades membrane-bound FGFR2 over other FGFR isoforms.
- LC-MB12 demonstrates superior potency in suppressing FGFR signaling and inhibiting proliferation compared to the parent inhibitor.
- LC-MB12 is orally bioavailable and exhibits significant antitumor activity in FGFR2-dependent gastric cancer xenografts.
Conclusions:
- LC-MB12 represents a potent and selective FGFR2 degrader with potential for alternative FGFR2-targeted cancer therapies.
- This molecule serves as a promising foundation for developing new drugs against FGFR2-driven malignancies.
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