Structure-Based Design of 2-Aminopyrazolpyrimidopyridone Derivatives as New Rearranged During Transfection (RET)
Jiayi Shen1, Jihu Liu1, Zhiyong Tan1
1Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University, Ganzhou, China.
Abstract:
RET (Rearranged during transfection) kinase is a validated target for non-small cell lung cancer (NSCLC). In 2020, two selective RET inhibitors, selpercatinib and pralsetinib were approved by the US FDA. However, high treatment costs and clinically acquired resistance (e.g., G810C/S/R) become the new challenges for RET-based therapies. In this work, we discovered a series of 2-aminopyrazolpyrimidopyridone RET inhibitors to overcome the V804M and G810C resistant mutations. One of the compounds, 8w, exhibited inhibitory potency against the BaF3 cells harboring CCDC6-RETV804M mutation with an IC50 value of 0.715 μM. The compound also dose-dependently suppressed the activation of RET and downstream signals. Another compound, 8s suppressed BaF3 cells harboring CCDC6-RETG810C mutation with an IC50 value of 2.91 μM. However, the poor solubility of these compounds will limit their further development. Therefore, compound 8w and 8s might be promising lead compounds for the development of novel RETV804M and RETG810C inhibitors overcoming the clinically acquired resistance.
Insights
New 2-aminopyrazolpyrimidopyridone inhibitors target resistant Rearranged during transfection (RET) kinase mutations in non-small cell lung cancer. Compounds 8w and 8s show promise against V804M and G810C mutations, respectively.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Rearranged during transfection (RET) kinase is a key target in non-small cell lung cancer (NSCLC).
- Approved RET inhibitors face challenges including high cost and acquired resistance mutations like V804M and G810C.
- Novel therapeutic strategies are needed to overcome resistance to current RET-targeted therapies.
Purpose of the Study:
- To discover novel 2-aminopyrazolpyrimidopyridone derivatives as RET inhibitors.
- To evaluate the efficacy of these compounds against clinically relevant RET resistance mutations (V804M and G810C).
- To identify promising lead compounds for further drug development.
Main Methods:
- Synthesis of a series of 2-aminopyrazolpyrimidopyridone compounds.
- In vitro evaluation of inhibitory activity against RET V804M and G810C mutations using BaF3 cell lines.
- Assessment of compound effects on RET activation and downstream signaling pathways.
Main Results:
- Compound 8w demonstrated potent inhibition of CCDC6-RETV804M with an IC50 of 0.715 μM and suppressed RET signaling.
- Compound 8s showed inhibitory activity against CCDC6-RETG810C with an IC50 of 2.91 μM.
- Both compounds exhibited dose-dependent suppression of RET activation and downstream signaling.
Conclusions:
- 2-aminopyrazolpyrimidopyridone derivatives are effective against RET V804M and G810C resistance mutations.
- Compounds 8w and 8s represent promising lead candidates for developing next-generation RET inhibitors.
- Further optimization is needed to address solubility limitations for clinical development.
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