bims-midomi 2026-03-01 papers

Cancers (Basel). 2026 Feb 07. pii: 546. [Epub ahead of print]18(4):

The Structure, Pathogenesis, and Inhibition of the p53-MDM2 Pathway.

Amanda L Brown, Xiaoying Lian, Qian Wang.

The p53 tumor suppressor protein plays a central role in maintaining genomic stability by regulating cell cycle arrest, apoptosis, and DNA repair under cellular stress. Mouse double minute 2 (MDM2), an E3 ubiquitin ligase, negatively regulates p53 via direct binding and proteasomal degradation. Overexpression or amplification of MDM2 can disrupt this pathway and promote tumorigenesis, even in cancers with wild-type p53. This review outlines the structural features of MDM2, particularly its N-terminal hydrophobic pocket and C-terminal RING domain, and their roles in p53 regulation. We further examine the pathological effects of MDM2 dysregulation and SNPs linked to increased cancer risk. Recent progress in small molecule MDM2 inhibitors is discussed, with a focus on non-covalent agents such as rhein-derived anthraquinone analogs, including AQ-101, which demonstrate promising anti-cancer activity with reduced toxicity. These findings support the continued development of non-covalent MDM2 inhibitors as a novel therapeutic approach for cancers involving both wild-type and mutant p53.

Keywords: MDM2 RING domain; MDM2 inhibition; non-covalent inhibition; p53; rhein-derived compounds; targeted therapy

DOI: https://doi.org/10.3390/cancers18040546

PLoS One. 2026 ;21(2): e0343551

Strategic selection of MDM2 inhibitors enhances the efficacy of FAK inhibition in mesothelioma based on TP53 genotype.

Xuerao Ning, Thảo Thi Thanh Nguyễn, Takao Morinaga, Yuji Tada, Hideaki Shimada, Kenzo Hiroshima, Naoto Yamaguchi, Masatoshi Tagawa.

Mesothelioma has characteristic genetic changes including inactivation of neurofibromatosis type 2 (NF2) and deletion of the INK4A/ARF region. Cells deficient of NF2 protein (MERLIN) depend on focal adhesion kinase (FAK) for cell adhesion and FAK inhibitors suppress the cell growth. The INK4A/ARF deletion activates MDM2 functions which ubiquitinate and degrade p53, and consequently the cellular p53 levels decrease. The deletion therefore induces loss of p53 functions although a majority of mesothelioma has wild-type TP53 genotype. An MDM2 inhibitor which blocked the ubiquitination increased p53 levels, restored p53 functions and facilitated cell growth arrest. Moreover, FAK and p53 expressions were reciprocally regulated. We examined growth suppressive effects of a FAK inhibitor, defactinib, and MDM2 inhibitors, nutlin-3a and reactivation of p53 and induction of tumor cell apoptosis (RITA), with representative wild-type and mutated TP53 mesothelioma and investigated molecular changes induced by the agents. We analyzed possible combinatory effects of the inhibitors and molecular changes caused by the combination. Our study showed that defactinib inhibited cell growth and induced FAK dephosphorylation irrespective of the TP53 genotype, and that the inhibited FAK phosphorylation was not associated with MERLIN levels or with p53 up-regulation, but linked with AKT dephosphorylation. Nutlin-3a preferentially suppressed growth of wild-type TP53 cells and augment p53 expression without DNA damage, whereas RITA-mediated p53 up-regulation was linked with the damage. A combination of defactinib and the MDM2 inhibitors showed that nutlin-3a showed synergistic/additive effects in wild-type and antagonistic effects in mutated TP53 cells, whereas RITA retained synergistic activity in mutated TP53 cells. These results suggest that the therapeutic success of combined FAK and MDM2 inhibition in mesothelioma depends on the precise matching of MDM2 inhibitors with the TP53 genotypes, and highlight the need for genotype-based selection of MDM2 inhibitors.

DOI: https://doi.org/10.1371/journal.pone.0343551

Cancer Res Commun. 2026 Feb 26.

Mutant Isocitrate dehydrogenase 1 sensitizes intrahepatic cholangiocarcinoma cells to MDM2 inhibitors.

Chien-Tsung Liu, Yung-Yeh Su, Nai-Jung Chiang, Chien-Feng Li, Yu-Chun Ma, Kung-Chao Chang, Yu-Hsuan Hung, Wen-Chun Hung, Li-Tzong Chen.

Mutations in isocitrate dehydrogenase 1 (IDH1) occur in 10-25% of intrahepatic cholangiocarcinoma (iCCA) cases. Despite significantly prolonged progression-free survival, the mutant IDH1 inhibitor ivosidenib achieved only a 3% response rate in clinical trials, highlighting the need for new therapeutic options for IDH1mut iCCA. Our in-silico analysis demonstrated that IDH1 mutation (IDH1mut) and TP53 mutation (TP53mut) were mutually exclusive in iCCA cells, and that IDH1mut iCCA cells expressed higher MDM2 levels than IDH1wt iCCA cells. Chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) assay showed enrichment of histone-3-lysine-4 tri-methylation (H3K4me3), an indicator of active gene transcription, at the MDM2 promoter in IDH1mut iCCA cells, confirming the data from ENCODE histone-seq. Treatment with a mutant IDH1 (mIDH1) inhibitor reduced 2-hydroxyglutarate (2-HG) levels, enhanced lysine-specific demethylase 5 (KDM5) activity, and attenuated the H3K4me3/H3K4me1 ratio at the MDM2 promoter, which was accompanied by a reduction in MDM2 expression and an increase in wild-type TP53 (wtTP53) protein levels in IDH1mut iCCA cells. The effect of mIDH1 inhibitor on MDM2 mRNA levels was reversed by treatment with KDOAM-25 citrate, a pan-KDM5 inhibitor. In addition, MDM2 inhibitors that could block MDM2-mediated wtTP53 degradation selectively induced TP53 reactivation, cell cycle arrest, and growth inhibition in IDH1mut iCCA cells. The combination of mIDH1 and MDM2 inhibitors synergistically suppressed the proliferation of IDH1wt iCCA cells. Our study delineated a novel mIDH1-MDM2-wtTP53 axis and its potential application of wtTP53 reactivation therapy in IDH1mut iCCA.

DOI: https://doi.org/10.1158/2767-9764.CRC-25-0591

Front Pharmacol. 2026 ;17 1715712

A novel pyrrolidine-chalcone derivative exhibits synergistic anti-cervical cancer activity by dual-targeting MDM2-p53 axis and ferroptosis pathway.

Hainimu Xiamuxi, XinYi Deng, Mourboul Ablise, Tong Yan, Madina Imam, Yu Wang, MingHui Zu, Wutiekuer Wumaier.

Introduction: Cervical cancer remains a serious threat to women's health, driving the need for effective and low-toxicity therapeutics. This study designed novel pyrrolidine-chalcone derivatives targeting the MDM2-p53 interaction.
Methods: A series of compounds were synthesized and evaluated for cytotoxicity against cervical cancer (HeLa, SiHa, C33A) and normal (H8) cells via CCK-8. The lead compound B1 was further analyzed for p53 pathway activation, apoptosis, and ferroptosis markers (ROS, GSH, MDA, Fe2+) using western blot, flow cytometry, and assay kits.
Results: Compound B1 showed potent, nanomolar cytotoxicity (IC50 = 0.22, 0.24, and 0.95 μM for HeLa, SiHa, and C33A, respectively) with low toxicity to H8 cells. B1 activated p53 by downregulating MDM2, inducing cell cycle arrest and apoptosis. Simultaneously, it triggered ferroptosis via ROS accumulation, GSH depletion, elevated MDA and Fe2+, and suppression of SLC7A11/GPX4.
Discussion: B1 is a promising dual-mechanism lead compound against cervical cancer, concurrently activating p53 and ferroptosis, warranting further investigation.

Keywords: MDM2-p53; cervical cancer; chalcone; ferroptosis; transcriptomics

DOI: https://doi.org/10.3389/fphar.2026.1715712

Curr Issues Mol Biol. 2026 Feb 04. pii: 177. [Epub ahead of print]48(2):

Simultaneous Inhibition of MDM2 and XIAP by MX69 Induced Cell Cycle Arrest and Apoptosis in HUH7 and Hep3B Cell Lines.

Can Ali Ağca.

Genomic instability not only drives tumor initiation and progression but also cooperates with apoptosis resistance to promote therapeutic evasion in hepatocellular carcinoma (HCC). Activation of MDM2, a negative regulator of p53, together with XIAP overexpression, represents a critical axis underlying this resistance. Simultaneous targeting of MDM2 and XIAP by MX69, a small molecule inhibitor, may therefore offer a potent interventional strategy to suppress cell proliferation and enhance pro-apoptotic signaling in HCC in vitro models. To evaluate the effects of MX69, cell viability was assessed via CVDK-8, colony formation, and real-time cell analysis. Oxidative stress levels and DNA damage were examined using fluorescence imaging and comet assays, respectively, while mitochondrial membrane potential was monitored through JC-1 staining. Furthermore, flow cytometry was employed to quantify apoptotic cell death and cell cycle distribution, while Western blot analysis was used to characterize the expression of apoptosis-related proteins. In vitro cytotoxicity assays revealed that MX69 reduced the viability of HUH7 and Hep3B cells in a dose-dependent manner, suppressed colony formation, and exerted anti-proliferative effects in real-time proliferation assays. Cell viability and IC50 values were evaluated using CVDK-8 and RTCA assays. Furthermore, MX69 induced oxidative stress and mitochondrial dysfunction, as evidenced by elevated ROS levels and loss of mitochondrial membrane potential. This was accompanied by significant DNA damage, detected by comet assay and γ-H2AX immunofluorescence, and G0-G1 cell cycle arrest. Moreover, MX69 triggered apoptotic cell death, demonstrating potent anticancer activity. Collectively, our findings identify MDM2/XIAP dual inhibition by MX69 as a promising therapeutic approach in HCC, with potential to overcome apoptosis resistance linked to genomic instability.

Keywords: DNA damage; HCC; MDM2/XIAP; MX69; apoptosis

DOI: https://doi.org/10.3390/cimb48020177