Cellular activity upregulation of the thermolabile p53 cancer mutant Y220C by small molecule indazole derivatives

  • Cell Death Discov. 2025 Nov 7;11(1):508. doi: 10.1038/s41420-025-02781-6.
Raniya Khadiullina  1 ,  Vitaly Chasov  1 ,  Elvina Gilyazova  1 ,  Damir Davletshin  1 ,  Regina Mirgayazova  1 ,  Rimma Mingaleeva  1 ,  Joseph R Stephenson Clarke  2 ,  Matthias Gj Baud  3 ,  Emil Bulatov  4  5
Affiliations
  • 1. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia.
  • 2. School of Chemistry and Chemical Engineering, University of Southampton, Southampton, UK.
  • 3. School of Chemistry and Chemical Engineering, University of Southampton, Southampton, UK. [email protected].
  • 4. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia. [email protected].
  • 5. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia. [email protected].
PMID: 41203614 DOI: 10.1038/s41420-025-02781-6
Abstract

The TP53 gene is one of the most frequently mutated genes in human cancers. Mutations often result in loss of tumor-suppressive functions and acquisition of oncogenic properties by p53, contributing to tumor progression and resistance to therapy. Among structural p53 mutations, Y220C is particularly notable for creating a surface-exposed hydrophobic pocket that destabilizes the protein while preserving partial function, making it a promising target for pharmacological reactivation. In this study, we performed a structure-guided phenotypic screen of an in-house heterocyclic compound library to identify novel small-molecule modulators of p53-Y220C. This led to the identification of a series of (1H-pyrrol-1-yl)indazole derivatives (JC16, JC36, JC65), structurally inspired by known Y220C Binders. JC16 and JC36 exhibited selective cytotoxicity and pro-apoptotic activity in p53-Y220C mutant Cancer cell lines, with minimal effects in wild-type or p53-null cells. These compounds induced a mutant-to-wild-type conformational shift in cellular p53-Y220C, accompanied by transcriptional activation of canonical p53 target genes, including BBC3 (PUMA) and MDM2. Western blot analysis revealed that in HUH7 cells, these effects occurred without a corresponding increase in total p53 protein levels, suggesting a mechanism based on conformational reactivation. Our findings position JC16 and JC36 as early-stage chemical leads with potential to restore mutant p53 function in a context-dependent manner. While their exact mechanism of action remains to be fully elucidated, these results provide a foundation for further development of indazole-based scaffolds as reactivators of the p53-Y220C mutant in Cancer therapy.

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