Bifunctional ligand design for modulating mutant p53 aggregation in cancer

Abstract

Iodination of a bifunctional ligand framework restores p53 function by interacting with and inhibiting mutant p53 aggregation.

Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function

“…Treatment with ReACp53 rescued p53 function in aggregation-prone mutant p53-bearing human ovarian and prostate cancer cells, leading to inhibition of cell proliferation in vitro and tumor shrinkage in vivo 14,41 . More recently, a bifunctional small molecule (denoted L I ), with a structure based on the amyloid reporter ThT, was reported to restore zinc binding in mutant p53 and to modulate its aggregation 80 . L I inhibited mutant p53 aggregation and restored the protein's transcriptional activity, leading to apoptosis in human gastric cancer cells in vitro.…”

Recent Synthetic Approaches towards Small Molecule Reactivators of p53

“…The effects were observed both in vitro and in tumoral cells. Also, the ligand presented minimal toxicity to non-cancerous organoids, showing a selective cytotoxicity to mutant p53 tumors [83].…”

A FRET-based fluorescent Zn2+sensor: 3D ratiometric imaging, flow cytometric tracking and cisplatin-induced Zn2+fluctuation monitoring

“…[1][2][3][4][5] Disorder in Zn 2+ homeostasis is associated with neurodegenerative diseases, cancer and immune defects. [6][7][8][9][10][11] As a powerful technology which can provide spatiotemporal information on Zn 2+ , uorescence imaging has been applied in living cells, tissues and model animals. [12][13][14][15][16] Imaging and monitoring labile Zn 2+ uctuation is intriguing yet challenging since the deviation of endogenous labile Zn 2+ homeostasis might be very small and dynamic.…”

“…31 Zn 2+ has been proposed to be involved in many of these pathways, including the p53 pathway. 10,32,33 Zinc deciency may not only induce an increase in oxidative stress that causes DNA damage but also affect the expression of DNA-repair protein apurinic endonuclease (APE) and the downstream signaling events. 9,34 We envisioned that intracellular Zn 2+ homeostasis would be disturbed by cisplatin treatment, and different Zn 2+ responses may be related to the sensitivity of cancer cells to cisplatin.…”