Discovery of Drugs Targeting Mutant p53 and Progress in Nano-Enabled Therapeutic Strategy for p53-Mutated Cancers

Abstract

Mutations in the p53 gene are frequently observed in various cancers, prompting the initiation of efforts to restore p53 function as a therapeutic approach several decades ago. Nevertheless, only a limited number of drug development initiatives have progressed to late-stage clinical trials, and to date, no p53-targeted therapies have received approval in the USA or Europe. This situation can be attributed primarily to the characteristics of p53 as a nuclear transcription factor, which lacks the conventional features associated with drug targets and has historically been considered "undruggable". In recent years, however, several promising strategies have emerged, including the enhanced iterations of previous approaches and novel techniques aimed at targeting proteins that have traditionally been considered undruggable. There is a growing interest in small molecules that can restore the tumor-suppressive functions of mutant p53 proteins, and the development of drugs specifically designed for particular p53 mutation types is currently underway. Other approaches aim to deplete mutant p53 or exploit vulnerabilities associated with its expression. Additionally, genetic therapy strategy and approaches have rekindled interest. Advances in mutant p53 biology, compound mechanisms, treatment modalities, and nanotechnology have opened up new avenues for p53-based therapies. However, significant challenges remain in clinical development. This review reassesses the progress in targeting p53-mutant cancers, discusses the obstacles in translating these approaches into effective therapies, and highlights p53-based therapies via nanotechnology.

Keywords: mutant p53; mutant p53 reactivation; nanodelivery; protein stability.

Figure 1

Schematic diagram of the functional domains of p53 (A) and MDM2 (B). (C) MDM2 maintains the functional stability of wtp53 by promoting its degradation and inhibiting its transcriptional activity. (D) Specific mutation sites of p53 (the data come from cBioPortal).

Figure 2

(A) The structures of some small-molecule compounds used for p53-mutated tumors; the chemical structures of the molecules were drawn by ChemDraw 22.0.0 64-bit. (B) The differential strategies to target p53-mutated tumors, including restoring the conformation of mutp53 by small-molecule compounds, inducing synthetic lethality, and clearing mutp53.

Figure 3

The discovered mechanisms underlying mutp53 protein stability and related intervention strategies. Disrupting the binding of mutp53 to molecular chaperones (DNAJA1 and HSP90), inhibiting 2-HG synthesis, targeting GSH reductase, or depleting GSH would promote the degradation of mutp53. Created by Figdraw.

Figure 4

Genetic therapy based on p53. The DNA or RNA encoding wtp53 could be delivered to cancer cells through various pathways, including recombinant viruses and nanoparticles, and promote the expression of wtp53 and the transcription of downstream target genes, thereby producing anticancer effects. In cancer cells with p53 mutations, the delivery of CRISPR-Cas9 along with appropriate guide RNA (gRNA) may achieve base editing and restore the wtp53 sequence. This graph was drawn by Microsoft Office PowerPoint (Office16) with reference to the previous literature [6].

Figure 5

Schematic illustration of the synthesis process of ZIF-8@MnO₂ nanoparticles and the mutp53 degradation mechanism. Reproduced with permission from [128]. Copyright 2024, Xangpeng Zheng et al. Advanced Science published by Wiley-VCH GmbH.

Figure 6

Schematic representation illustrating the synthesis of crizotinib/Dox-loading nanomicelles and the synergistic therapy of Dox and crizotinib for mutp53-driven cancer. Reproduced with permission from [130]. Copyright 2023, American Chemical Society.

Figure 7

Schematic illustration of the synthesis and the treatment mechanism via synthetic lethality of ADA@MOF-EPL. Reproduced with permission from [139]. Copyright 2024, Science China Pres. Published by Elsevier B.V. and Science China Press.