bims-midomi 2025-10-12 papers

Sci Rep. 2025 Oct 06. 15(1): 34687

In silico identification of prospective p53-MDM2 inhibitors from ASINEX database using a comprehensive molecular modelling approach.

Dushyant D Kotadiya, Apurva Prajapati, Dharmesh A Patel, Pooja Thakur, Ruchi Nair, Hitesh D Patel.

Cancer cells have a higher evolutionary potential than normal cells, which commonly leads to medication resistance and a decrease in the efficacy of existing cancer treatments. As a result, discovering new therapeutic drugs is an important priority in the field of oncology. The tumor suppressor protein p53, regulates many cellular activities but is frequently rendered inactive in malignancies due to aberrant overproduction of MDM2 and MDMX. As a result, the method of targeting MDM2 with small-molecule inhibitors to reactivate p53 signalling has gained popularity as a promising approach for anticancer drug development. In this study, we performed a comprehensive structure-based virtual screening of 261,120 compounds from the Asinex database, along with molecular docking, ADMET profiling, and molecular dynamics (MD) simulations using Schrödinger's Maestro platform, to identify high-affinity MDM2 binders. electronic properties and stability characteristics have been assessed using Density Functional Theory (DFT) computations. The generated lead compounds had favourable pharmacokinetic features and high binding affinities for MDM2, making them suitable scaffolds for further therapeutic study. Overall, our findings lay the groundwork for experimental validation and drive the hunt for next-generation inhibitors of the p53-MDM2 pathway in cancer therapy.

Keywords: ADMET; DFT; Molecular Docking; Molecular dynamics; P53-MDM2 inhibitors; Virtual screening

DOI: https://doi.org/10.1038/s41598-025-10589-8

FASEB J. 2025 Oct 15. 39(19): e71093

Characterizing Elephant MDM2's Role in p53 Regulation.

Emma Palefsky, Himani K Patel, Trey A Doss, Emilye C Eischeid, Paul Lee, MacLaren A Durkee, William H Yang, Avery M Duncan, Darshti Patel, Anmol P Patel, Wei-Hsiung Yang, Jong-Hyuk Lee.

Peto's paradox, which describes the absence of a strong correlation between cancer risk, body size, and lifespan among species, raises intriguing questions about natural cancer resistance mechanisms. Elephants have evolved unique adaptations that reduce cancer susceptibility despite their large body size and long lifespan. Central to this phenomenon is p53, a key tumor suppressor regulated by MDM2. Our research investigates the structural and functional differences between elephantine MDM2 and its human counterpart. Utilizing human cellular models, we demonstrate that elephantine MDM2 variants enhance p53's activity, leading to increased p53 occupancy on its response elements, and modulate p53-mediated transcription in a stress-dependent manner. These findings shed light on the molecular basis of cancer resistance in elephants and provide a foundation for developing innovative cancer therapies targeting MDM2-p53 interactions.

Keywords: BAX; MDM2; Peto's paradox; TP53 retrogene; cancer resistance; elephants; p21; p53; transcriptional regulation; tumor suppressor

DOI: https://doi.org/10.1096/fj.202502511R

J Pathol. 2025 Oct 09.

DNA-hypermethylated human gastric cancer circumvents apoptosis in the absence of TP53 mutation.

Yasunobu Mano, Keisuke Matsusaka, Motoaki Seki, Kazuko Kita, Masaki Fukuyo, Bahityar Rahmutulla, Genki Usui, Ryoji Fujiki, Masayuki Urabe, Hiroyuki Abe, Hisahiro Matsubara, Tetsuo Ushiku, Yasuyuki Seto, Masashi Fukayama, Atsushi Kaneda.

p53 is one of the most important tumour suppressors exerting antitumour effects primarily via apoptosis. TP53 mutations are common in gastric tumorigenesis; however, nearly half of the gastric cancers (GCs) remain wildtype TP53 (TP53_WT). We investigated epigenetic/genetic profiles of GCs and the carcinogenic mechanisms underlying GCs with TP53_WT. Comprehensive DNA methylation analysis revealed four DNA methylation epigenotypes (MEs) in GCs, namely, high ME (HME), extremely HME (E-HME), low ME (LME), and extremely LME (E-LME). E-HME matched Epstein-Barr virus (EBV)-positive GC (E-HME/EBV). HME can be further categorised into MLH1-deficient (HME_MLH1(-)) and -proficient cases. The Cancer Genome Atlas data confirmed that HME_MLH1(-)/microsatellite instability (MSI) and E-HME/EBV cases significantly retained TP53_WT and had higher MDM2 expression levels than other MEs. We hypothesised that apoptosis pathways in TP53_WT GC may be suppressed post-transcriptionally by activated MDM2. Short hairpin RNA-mediated MDM2 knockdown and the p53-MDM2 inhibitors, nutlin-3 and RG7388, induced apoptosis in TP53_WT GC cells, indicating that activated MDM2 suppressed p53 protein levels and thereby attenuated the downstream p53 pathway activation, which was restored upon MDM2 knockdown or inhibitor treatment. Collectively, DNA-hypermethylated GC cases, HME_MLH1(-)/MSI and E-HME/EBV, follow a unique carcinogenic pathway to evade apoptosis in the absence of TP53 mutation, potentially making them responsive to therapeutic strategies that function primarily through the p53 pathway. © 2025 The Pathological Society of Great Britain and Ireland.

Keywords: DNA methylation epigenotype; Epstein–Barr virus; MDM2; apoptosis; gastric cancer; microsatellite instability; p53

DOI: https://doi.org/10.1002/path.6480

Biol Pharm Bull. 2025 ;48(10): 1485-1492

Quercetin, a Natural Dietary Flavonoid, Emerges a Novel USP7 Inhibitor with Anti-colorectal Cancer Effects.

Xue Li, Qiyan Li, Ying Huang, Heyang Zhou, Qianqing Yang, Lingmei Kong.

The human deubiquitinating enzyme ubiquitin-specific peptidase 7 (USP7) has emerged as a promising anti-tumor target, particularly in colorectal cancer, due to its regulation of the MDM2/p53 axis. Through a combination of ubiquitin C-terminal 7-amido-4-methylcoumarin hydrolysis assay and ubiquitin-propargylamide protease profiling, we identified the natural dietary flavonoid quercetin as a potent USP7 inhibitor in both cell-free and cellular contexts. Cellular thermal shift and surface plasmon resonance analyses demonstrated that quercetin is directly bound to USP7. Consistent with USP7 target engagement in cells, quercetin decreased MDM2 levels and subsequently increased the levels of p53. Moreover, quercetin also suppressed colorectal cancer cell proliferation by inducing G2/M cell cycle arrest and inhibiting cell migration. Collectively, our study identified quercetin as a novel and effective USP7 inhibitor with potent anti-colorectal cancer activity, highlighting its therapeutic potential for targeting the USP7-MDM2-p53 axis and warranting further exploration as a promising therapeutic agent in colorectal cancer treatment.

Keywords: colorectal cancer; novel inhibitor; p53; quercetin; ubiquitin-specific peptidase 7

DOI: https://doi.org/10.1248/bpb.b25-00435

Cell Oncol (Dordr). 2025 Oct 06.

A novel β-carboline alkaloid derivative targeting MDM2-p53 pathway suppresses colorectal cancer progression.

Fanbin Zeng, Cheng Chen, Zhanwei Fu, Haihui Huang, Wenqiang Cui, Yuanyuan Zhou, Yanjie Kong, Xia Liu, Zhiru Xu, Shouguo Wang, Tian Xiao, Houjun Xia.

PURPOSE: Colorectal cancer (CRC) remains a major global health challenge, necessitating novel therapeutic approaches. β-carboline alkaloids, natural compounds with anticancer properties, have shown potential to inhibit cancer cell viability. Here, we synthesized β-carboline derivatives and explored their potential as CRC inhibitors.
METHODS: The IC50 values of β-carboline derivatives were determined by cell viability assay. The biological effects of the leading candidate were evaluated via cell cycle analysis, proliferation assay, colony formation, apoptosis assay, and reactive oxygen species detection. Mechanistic studies were performed using transcriptomic and proteomic analysis, validated by immunoblotting, pulldown assay, cycloheximide-chasing assay, and co-immunoprecipitation. An in vivo CRC xenograft model was used to assess the efficacy of the leading candidate.
RESULTS: Z-7 was identified as the leading candidate due to its ability to induce apoptosis and cell cycle arrest in CRC cells. Transcriptomic and proteomic data revealed that Z-7 activated the p53 signaling pathway in p53 wild-type CRC by binding to MDM2 at the RING domain, and inhibiting the E3 ligase activity of MDM2, leading to the reduction of p53 ubiquitination. In vivo study showed Z-7 treatment elevated p53 expression and significantly suppressed tumor growth in xenograft models.
CONCLUSION: Z-7 is a promising candidate for CRC therapy, particularly in patients with functional p53 and elevated MDM2, warranting further clinical evaluation.

Keywords: Colorectal cancer; MDM2-p53 pathway; Small-molecule compounds; β-carboline alkaloid

DOI: https://doi.org/10.1007/s13402-025-01111-3