McCubrey James A, Follo Matilde Y, Ratti Stefano, Martelli Alberto M, Manzoli Lucia, Augello Giuseppa, Cervello Melchiorre, Cocco Lucio
Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
Adv Biol Regul. 2025 Jan;95:101073. doi: 10.1016/j.jbior.2024.101073. Epub 2024 Dec 28.
TP53 is normally a tumor suppressor. However, it is mutated in at least 50% of human cancers. Usually, we assume that mutation of the TP53 is associated with loss of sensitivity to various drugs as in most cases wild type (WT) TP53 activity is lost. This type of mutations is often dominant-negative (DN) mutations as they can interfere with the normal functions of WT-TP53 which acts as a tetramer. These mutations can result in altered gene expression patterns. There are some TP53 mutations which may lack some of the normal functions of TP53 but have additional functions; these types of mutations are called gain of function (GOF) mutations. There is another class of TP53 mutations, they are TP53 null mutations as the cells have deleted the TP53 gene (TP53-null). Although TP53 mutations were initially considered undruggable, other approaches have been developed to increase TP53 activity. One approach was to develop mouse double minute 2 homolog (MDM2) inhibitors as MDM2 suppresses TP53 activity. In addition, there have been mutant TP53 reactivators created, which will at least partially restore some of the critical growth suppressing effects of TP53. Some of these mutant TP53 reactivators have shown promise in clinical trial in certain types of cancer patients, especially myelodysplastic syndrome (MDS). In this review, we summarize the development of novel TP53 reactivators and MDM2 inhibitors. Both approaches are aimed at increasing or restoring TP53 activity. Attempts to increase TP53 activity in various TP53 mutant tumors could increase therapy of multiple deadly diseases.
TP53通常是一种肿瘤抑制因子。然而，它在至少50%的人类癌症中发生了突变。通常，我们认为TP53的突变与对各种药物的敏感性丧失有关，因为在大多数情况下野生型（WT）TP53的活性丧失了。这种类型的突变通常是显性负性（DN）突变，因为它们会干扰作为四聚体发挥作用的WT-TP53的正常功能。这些突变可导致基因表达模式改变。有一些TP53突变可能缺乏TP53的一些正常功能，但具有额外功能；这些类型的突变被称为功能获得（GOF）突变。还有另一类TP53突变，它们是TP53无效突变，因为细胞已经删除了TP53基因（TP53缺失）。尽管TP53突变最初被认为是不可成药的，但已经开发出了其他方法来提高TP53的活性。一种方法是开发小鼠双微体2同源物（MDM2）抑制剂，因为MDM2会抑制TP53的活性。此外，还产生了突变型TP53激活剂，它们将至少部分恢复TP53的一些关键生长抑制作用。其中一些突变型TP53激活剂在某些类型癌症患者的临床试验中，尤其是骨髓增生异常综合征（MDS）中显示出了前景。在这篇综述中，我们总结了新型TP53激活剂和MDM2抑制剂的发展情况。这两种方法都旨在提高或恢复TP53的活性。在各种TP53突变肿瘤中提高TP53活性的尝试可能会增加对多种致命疾病的治疗。
