scholarly journals MDM2 inhibitors: Targeting p53-MDM2 interaction to anti-cancer

2021 ◽  
Vol 308 ◽  
pp. 02015
Author(s):  
Xulin Zhang

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.

2005 ◽  
Vol 25 (18) ◽  
pp. 7953-7965 ◽  
Author(s):  
Li Wang ◽  
Robert A. Baiocchi ◽  
Sharmistha Pal ◽  
George Mosialos ◽  
Michael Caligiuri ◽  
...  

ABSTRACT Mutation of BRG1, hBRM, and their associated factors, INI1 and BAF57, in primary human tumors has suggested that inactivation of human SWI/SNF (hSWI/SNF) complexes may be involved in neoplastic transformation. BT549 is an invasive human breast carcinoma cell line that lacks expression of BAF57, a key hSWI/SNF subunit that mediates interaction with transcriptional activators and corepressors. In this study we investigated the role of BAF57 in suppressing tumorigenesis by establishing BT549 stable cell lines that expresses full-length BAF57 protein. BT549 clones expressing BAF57 demonstrated marked phenotypic changes, slow growth kinetics, and restoration of contact inhibition. Altered growth was found to be due in part to cell cycle arrest and induction of apoptosis. Furthermore, microarray analysis revealed that BAF57-mediated cell death was associated with up-regulation of proapoptotic genes including the tumor suppressor familial cylindromatosis (CYLD), which was found to be a direct target of BAF57 as determined by chromatin immunoprecipitation analysis. Increased expression of CYLD in BT549 cells induced apoptosis, while its suppression by small interfering RNA inhibited cell death in BAF57 expressing BT549 cells. These findings demonstrate the importance of BAF57 in cell growth regulation and provide a novel link between hSWI/SNF chromatin remodelers and apoptosis.


Medicinus ◽  
2018 ◽  
Vol 5 (1) ◽  
Author(s):  
Jacobus Jeno Wibisono

<p><em>Cervical cancer is one of the most prevalent cancer in the world and caused by Human Papilloma Virus (HPV). The pathogenesis of cancer as whole (50%) is caused by gene mutation. HPV stimulates carcinogenesis on cervix epitel cells by HPV-Encoded viral oncoproteins, E6 and E7, which will inhibit tumor suppressor gene activation, such as p53 gene. HPV-encoded E6 oncoprotein  is able to directly attached on p53 causing degeneration via E6-AP-mediated ubiquitination pathway. Moreover, overexpression on YY1 gene has significant role on the progression of HPV on cervical cancer. YY1 inhibits p53 activation dan inhibits apoptosis on cells infected by HPV. Overexpression of YY1 induces reduction of endogenous p53, which will inhibit p53 function as tumor suppressor gene.</em></p><p><strong><em>Keywords: cervical cancer, HPV, P53, YY1</em></strong></p>


2015 ◽  
Vol 149 (3) ◽  
pp. 693-703 ◽  
Author(s):  
Marleen Ansems ◽  
Jonas Nørskov Søndergaard ◽  
Anieta M. Sieuwerts ◽  
Maaike W. G. Looman ◽  
Marcel Smid ◽  
...  

2006 ◽  
Vol 66 (7) ◽  
pp. 3419-3427 ◽  
Author(s):  
Juliana J. Oh ◽  
Ali Razfar ◽  
Idolina Delgado ◽  
Rebecca A. Reed ◽  
Anna Malkina ◽  
...  

2021 ◽  
Vol 22 (18) ◽  
pp. 9795
Author(s):  
Hyunho Kim ◽  
Byoung Yong Shim ◽  
Seung-Ju Lee ◽  
Ji Youl Lee ◽  
Hyo-Jin Lee ◽  
...  

Renal cell carcinoma (RCC) is a malignancy of the kidney originating from the tubular epithelium. Inactivation of the von Hippel–Lindau tumor-suppressor gene (VHL) is found in most clear cell renal cell carcinomas (ccRCCs). The VHL–HIF–VEGF/VEGFR pathway, which involves the von Hippel–Lindau tumor suppressor protein (VHL), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), and its receptor (VEGFR), is a well-studied therapeutic target for metastatic ccRCC. Therefore, over the past decade, anti-angiogenic agents targeting VEGFR have served as the standard treatment for metastatic RCC. Recently, based on the immunomodulatory effect of anti-VEGFR therapy, anti-angiogenic agents and immune checkpoint inhibitor combination strategies have also emerged as therapeutic strategies. These advances were made possible by the improved understanding of the VHL–HIF pathway. In this review, we summarize the historical evolution of ccRCC treatments, with a focus on the involvement of the VHL–HIF pathway.


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