1. Design, synthesis and antitumor activity of a novel FGFR2-selective degrader to overcome resistance of the FGFR2V564F gatekeeper mutation based on a pan-FGFR inhibitor.
- Author
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Hu, Zuli, Zhang, Qiangsheng, Li, Zulong, Yang, Hongling, Chen, Xin, Zhang, Qi, Yang, Tianqiong, He, Xiaojie, Feng, Qiang, He, Jun, and Yu, Luoting
- Subjects
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FIBROBLAST growth factor receptors , *ANTINEOPLASTIC agents , *GATEKEEPERS , *INHIBITION of cellular proliferation - Abstract
Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC 50 = 0.645 nM, DC max = 86 %). Compound 28e selectively degraded FGFR2 and essentially avoided degradation of FGFR1,3,4 isoforms (DC 50 > 300 nM). Compound 28e significantly inhibited the proliferation of FGFR2-overexpressing cell lines, including KATOIII, SNU16, and AN3CA (IC 50 = 0.794 nM/0.207 nM/4.626 nM), comparable to parental inhibitors. At the same time, the preferred compound showed superiority over the parental inhibitor in kinase inhibitory activity against the gatekeeper mutant isoform FGFR2V564F (IC 50 = 0.121 nM). In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents. [Display omitted] • A series of novel FGFR2-selective degraders were designed and synthesized based on pan-FGFR inhibitor. • 28e exhibited the ability to efficiently degrade FGFR2 isoform with DC 50 of 0.645 nM. • 28e selectively degraded FGFR2 isoform but not FGFR1/3/4 isoforms. • 28e had the potential to overcome the FGFR2V564F gatekeeper resistance mutation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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