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Design and Synthesis of 2-Aminopyrazolpyrimidopyridone Derivatives as RETV 804M and RETG 810C Kinase Inhibitors
Jiayi Shen1, Anzhi Li1, Jieman Lin1
1Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, Gannan Normal University, Ganzhou, China.
Abstract:
Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is associated with several cancers. The clinical therapeutic benefits of the second-generation RET inhibitor pralsetinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RETG810R/S/C). Herein, a class of 2-aminopyrazolpyrimidopyridone derivatives as RETV804M and RETG810C solvent-front mutant inhibitors were designed and synthesized for overcoming pralsetinib resistance. One of the optimal compounds, 7la, exhibited inhibitory potency against the proliferation of BaF3 cells harboring CCDC6-RETV804M mutation with IC50 values of 0.271 μM. Interestingly, another one of these series compounds, 7qe, suppressed BaF3 cells harboring CCDC6-RETV804M and CCDC6-RETG810C mutations with IC50 values of 0.841 and 0.272 μM, respectively. The compound also dose-dependently suppressed the activation of RET and downstream signals. However, the relatively poor pharmacokinetic properties of these compounds will limit their further development. Therefore, compound 7qe might be a promising lead compound for the development of novel RETV804M and RETG810C inhibitors overcoming the clinical acquired resistance.
Insights
New 2-aminopyrazolpyrimidopyridone derivatives were developed to overcome acquired resistance to RET inhibitors like pralsetinib. Compound 7qe shows promise as a lead for novel inhibitors targeting RET V804M and G810C mutations in cancer.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- The rearranged during transfection (RET) tyrosine kinase is oncogenic in several cancers.
- Acquired resistance to RET inhibitors, such as pralsetinib, often involves solvent-front mutations (e.g., RETG810R/S/C), limiting therapeutic efficacy.
Purpose of the Study:
- To design and synthesize novel 2-aminopyrazolpyrimidopyridone derivatives as inhibitors of RETV804M and RETG810C solvent-front mutants.
- To overcome pralsetinib resistance mediated by these specific RET mutations.
Main Methods:
- Synthesis of a series of 2-aminopyrazolpyrimidopyridone derivatives.
- In vitro evaluation of inhibitory potency against BaF3 cells harboring CCDC6-RETV804M and CCDC6-RETG810C mutations.
- Assessment of compound effects on RET activation and downstream signaling pathways.
Main Results:
- Compound 7la demonstrated inhibitory activity against RETV804M (IC50 = 0.271 μM).
- Compound 7qe effectively suppressed cells with RETV804M (IC50 = 0.841 μM) and RETG810C (IC50 = 0.272 μM) mutations.
- Compound 7qe dose-dependently inhibited RET activation and downstream signaling.
Conclusions:
- The synthesized 2-aminopyrazolpyrimidopyridone derivatives show potential for overcoming pralsetinib resistance.
- Compound 7qe is identified as a promising lead compound for developing novel RETV804M and RETG810C inhibitors, despite limitations in pharmacokinetic properties.
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