Synthesis and Antineoplastic Activity of a Dimer, Spiroindolinone Pyrrolidinecarboxamide

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Tumour suppressor p53 is crucial for preventing abnormal cell proliferation and cancer.
• Murine Double Minute 2 (MDM2) negatively regulates p53, making MDM2-p53 interaction inhibition a therapeutic strategy.
• Developing effective MDM2 inhibitors with reduced toxicity is essential for cancer treatment.

Purpose of the Study:

• To synthesize and evaluate a novel spiroindolinone pyrrolidinecarboxamide dimer, XR-4, as a potent MDM2 inhibitor.
• To investigate the anti-cancer effects of XR-4, including its impact on p53 pathway and cancer cell proliferation.
• To assess the in vivo anti-tumour efficacy and safety profile of XR-4.

Main Methods:

• Synthesis of XR-4, a spiroindolinone pyrrolidinecarboxamide dimer.
• Western blotting and qRT-PCR to analyze MDM2, p53, and downstream target gene expression.
• Cell proliferation (CCK8 assay) and clonogenic assays to assess anti-cancer effects.
• In vivo anti-tumour activity evaluation using a 22Rv1 xenografts mice model.

Main Results:

• XR-4 induced wild-type p53 accumulation and upregulated p53 target genes (p21, PUMA) in cancer cells.
• XR-4 inhibited cancer cell proliferation and induced apoptosis.
• XR-4 demonstrated homo-PROTAC activity, leading to MDM2 protein degradation.
• In vivo studies confirmed XR-4's potent anti-tumour efficacy and favourable safety.

Conclusions:

• XR-4 is a novel spiroindolinone pyrrolidinecarboxamide dimer with potent p53-reactivating and anti-cancer properties.
• XR-4 effectively inhibits cancer cell proliferation and induces apoptosis through p53 activation and MDM2 degradation.
• XR-4 exhibits promising therapeutic potential for cancer treatment with a favorable safety profile.