School of Pharmacy, Faculty of Health & Medical Sciences, Taylor's University, 1, Jalan Taylors, 47500, Subang Jaya, Selangor, Malaysia.
Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, 50603, Jln Profesor Diraja Ungku Aziz, Seksyen 13, 50603, Kuala Lumpur, Malaysia.
Curr Mol Pharmacol. 2024;17(1):e140923221042. doi: 10.2174/1874467217666230914090621.
Mutations in the TP53 gene are the most common among genetic alterations in human cancers, resulting in the formation of mutant p53 protein (mutp53). Mutp53 promotes proliferation, migration, invasion, and metastasis in cancer cells. Not only does the initiation of oncogenesis ensue due to mutp53, but resistance towards chemotherapy and radiotherapy in cancer cells also occurs. This review aims to summarise and discuss the oncogenesis of mutant p53 in cancer cells and introduce the various mutant p53 inhibitors currently being evaluated at the pre-clinical and clinical stages. Compounds that induce the wild-type conformation on the targeted p53 missense mutation, restore or enhance the DNA binding of mutant p53, and inhibit cancer cells' growth are highlighted. In addition, the progression and development of the mutant p53 inhibitors in clinical trials are updated.
The progress of developing a cancer treatment that may successfully and efficiently target mutant p53 is on the verge of development. Mutant p53 proteins not only initiate oncogenesis but also cause resistance in cancer cells to certain chemo or radiotherapies, further endorse cancer cell survival and promote migration as well as metastasis of cancerous cells. With this regard, many mutant p53 inhibitors have been developed, some of which are currently being evaluated at the pre-clinical level and have been identified and discussed. To date, APR-246 is the most prominent one that has progressed to the Phase III clinical trial.
TP53 基因突变是人类癌症中最常见的遗传改变之一，导致突变型 p53 蛋白（mutp53）的形成。mutp53 促进癌细胞的增殖、迁移、侵袭和转移。不仅由于 mutp53 导致了致癌作用的启动，而且癌细胞对化疗和放疗也产生了抵抗。本综述旨在总结和讨论突变型 p53 在癌细胞中的致癌作用，并介绍目前在临床前和临床阶段评估的各种突变型 p53 抑制剂。重点介绍了诱导靶向 p53 错义突变的野生型构象、恢复或增强突变型 p53 的 DNA 结合以及抑制癌细胞生长的化合物。此外，还更新了突变型 p53 抑制剂在临床试验中的进展。
开发一种可能成功且有效地针对突变型 p53 的癌症治疗方法的进展即将取得突破。突变型 p53 蛋白不仅启动了致癌作用，而且使癌细胞对某些化疗或放疗产生了抵抗，进一步促进了癌细胞的存活，并促进了癌细胞的迁移和转移。在这方面，已经开发了许多突变型 p53 抑制剂，其中一些目前正在进行临床前评估，并已被确定和讨论。迄今为止，APR-246 是进展到 III 期临床试验的最突出的一个。
