Abstract
P53 is a recognized tumor suppressor gene, which mainly depends on the activity of its transfer factor to realize the tumor suppressor effect. Mouse two-minute 2 (MDM2) is an important inhibitor of p53. When combined with MDM2, the activity of p53 will be reduced, and the anti-cancer effect will be weakened. According to the mechanism between p53 and MDM2, researchers focus on the inhibitors to inhibit their binding. Through a large number of drug screening methods and means, this article has found many new inhibitors of p53-MDM2 interaction, most of which are still in the clinical research stage. Specifically, we classify the drugs based on their different action mechanisms. Firstly, some drugs combine with MDM2 to inhibit the p53-MDM2 interaction. They are Siremadlin (NVP-HDM201), RG7112, and NVP-CGM09. While some act on p53, they rely on their induction of p53 signalling and inhibition of tumour cell proliferation in p53 wild-type tumor cell lines, like MK-8242 and KRT-232(AMG-232). What’s more, one inhibitor’s action bases on P53 and MDM2 in T cells is APG-115. And last but not least, there are also several drugs that stable tumor suppressor TP53, leading to p53 activation and inducing cell cycle arrest and apoptosis, they are Idasanutlin (RG7388) and Milademetan (DS-3032/RAIN-32). Furthermore, clinical studies are finding that monotherapy does not deliver a powerful therapeutic effect. Various combination strategies are being explored with MDM2 inhibitors preclinically and in the clinic. This article will talk about some specific combinations: APG-115 combine with immune checkpoint inhibitor PD-1/PD-L1, MDM2 inhibitors combine with BCL-2 inhibitors, anti-CD20 therapeutic antibodies, and the last, combine with alkylating agents.
Highlights
In the current decades, the malignant tumor has been a serious threat to human health
We turned to another drug called NVP-CGM097, an effective and specific murine double minute 2 (MDM2) inhibitor that binds to human MDM2 and shows high selectivity over MDM4
APG-115-stimulated immunity is able to sensitize resistant tumors to programmed cell death 1 (PD-1) blockade into sensitive tumors, and such a therapy approach may apply to both Trp53wt and Trp53mut tumors, creating a significant impact [41]
Summary
The malignant tumor has been a serious threat to human health. The TP53 gene was found mutated or deleted in around half of the human cancer cells, indicating the importance of p53 in suppressing tumors [2]. Its expression can up-regulate various cancers, leading to loss of p53-dependent activities, such as apoptosis and cell cycle arrest [3]. It plays a key role in controlling its transcriptional activity, protein stability, and nuclear localization. Once SUMO binds to MDM2, its E3 ligase activity changes towards ubiquitination of p53, with its ubiquitination being minimal. Overexpression or amplification of MDM2 can significantly reduce the level of p53 expressed in cells, inhibiting the tumor suppression of p53 and lead to malignancies. We conducted some further combination therapy research to enhance the inhibition effect on the cancer cell
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