bims-midomi 2026-02-22 papers

Phys Chem Chem Phys. 2026 Feb 20.

Triazole-stapled p53 mimetics as MDM2 inhibitors: structural and thermodynamic origin of enhanced binding affinity.

Vikram Gaikwad, Pushyaraga P Venugopal, Rajarshi Chakrabarti.

The p53-MDM2 protein-peptide complex is central to oncogenic-targeted therapeutics. p53 functions as a regulatory protein involved in DNA repair and cell cycle control, while MDM2 acts as its negative regulator. In oncogenic conditions, disrupting the p53-MDM2 interaction presents a significant therapeutic challenge. Stapled peptides, particularly triazole-based peptides, exhibit enhanced stability and binding affinity, making them promising inhibitors and potential alternatives to conventional therapeutics. However, their detailed binding mechanism and thermodynamic aspects remain underexplored. In this study, we built and refined peptide models, after which extensive simulations were performed to investigate the binding of triazole-based stapled p53 peptides to MDM2. Among the variants studied, the p534-11 peptide exhibited the most favorable binding free energy, primarily due to an extended number of non-covalent interactions, and it is in good agreement with the experiment. We also examined the role of water molecules in the binding process. Our results reveal that water plays a crucial role in mediating bridging interactions between p53 and MDM2, and these interactions were particularly substantial in the p534-11 complex. These findings provide valuable insights for the rational design of future triazole-stapled peptides and can guide future experimental efforts in targeting the p53-MDM2 interaction.

DOI: https://doi.org/10.1039/d5cp03813h

J Bioinform Comput Biol. 2026 Feb;24(1): 2651001

Analysis of the regulation of model parameters on delay time in the p53 dynamical response to single-stranded breaks.

Aiqing Ma, Xiyan Yang.

The dynamic p53 response is a known determinant of cell fate. However, its temporal control, specifically the mechanisms regulating the delay time ([Formula: see text]) of the graded p53 pulse following single-stranded breaks (SSBs), remains poorly understood. To systematically dissect this timing mechanism, we developed and analyzed a mechanistic ordinary differential equation (ODE) model of the p53-Mdm2-ATR network. We first established that increasing damage intensity reliably shortens the delay time, accelerating the cellular decision-making process. Our analysis revealed a critical finding: the delay time is most acutely sensitive to the p53-dependent Mdm2 production rate ([Formula: see text]), highlighting the dominant role of the negative feedback loop in setting the pace. We further classified the model parameters into functional roles: accelerators (e.g. Ataxia-Telangiectasia and RAD3-related (ATR) production rate dependent on damage ([Formula: see text]), p53 activation rate dependent on ATR ([Formula: see text]), p53-dependent Mdm2 production rate ([Formula: see text]), p53-dependent Wip1 production rate ([Formula: see text], ATR degradation rate ([Formula: see text]) and Mdm2-dependent p53 degradation rate ([Formula: see text], which shorten the delay time ([Formula: see text]), and brakes (e.g. ATR-dependent Mdm2 degradation rate ([Formula: see text]), self-degradation rate of Mdm2 ([Formula: see text]) and self-degradation rate of Wip1 ([Formula: see text]), which prolong it. Sensitivity analysis showed that as parameter values increase, [Formula: see text] becomes less sensitive to [Formula: see text]. The sensitivity to [Formula: see text] exhibited an initial increase followed by a decrease, whereas the opposite trend was observed for [Formula: see text]. The remaining parameters ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]) all showed a monotonic decrease in sensitivity. This work provides a quantitative blueprint for therapeutic interventions, suggesting that targeting the p53-Mdm2 feedback strength is the most effective strategy to sensitize cancer cells and shorten the critical delay to cell death.

Keywords: DNA single-stranded breaks; delay time; p53 graded response; sensitivity analysis

DOI: https://doi.org/10.1142/S0219720026510017

ACS Med Chem Lett. 2026 Feb 12. 17(2): 450-457

Synthesis and Biological Evaluation of a Novel Dual-Targeting Small Molecule Drug Conjugate Modulating the Crosstalk between α5β1 Integrin and MDM2 in Glioblastoma.

Federico Arrigoni, Ana Ferrari, Helena Prpić, Elena Markeviciute, Alessia Muzi, Giuseppe Roscilli, Silvia Gazzola, Umberto Piarulli.

Negative crosstalk between α5β1 integrin and the p53-MDM2 regulatory axis contributes to glioblastoma progression and therapeutic resistance. To explore the potential of dual inhibition of these two biological targets, the dual targeting small molecule drug conjugate (SMDC) (1) was designed by coupling the MDM2 inhibitor SAR405838 to a selective α5β1 integrin ligand cyclo(phg-isoDGR-k) (7) through a stable chemical linker. The resulting conjugate retained antiproliferative activity in U87-MG glioblastoma cells and induced p53 reactivation with minimal MDM2 induction. Cell cycle distribution analysis revealed a redistribution of cells from the G0/G1 phase to the G2/M phase exclusively upon treatment with conjugate 1, suggesting that a different mechanism of action is engaged. These findings support the potential of this dual-targeting approach through a dual-targeting SMDC as a promising therapeutic strategy against high-grade glioma overexpressing the α5β1 integrin receptor.

Keywords: MDM2 inhibitor; cross-talk; drug conjugate; dual-targeting SMDC; glioblastoma; p53; α5β1 integrin

DOI: https://doi.org/10.1021/acsmedchemlett.5c00669

World J Diabetes. 2026 Feb 15. 17(2): 112500

Formononetin inhibits p53 signaling pathway activation to delay cellular senescence and ameliorates diabetic kidney disease.

Yue Ji, Rui-Xin Liu, Pei-Yue He, Yi-Min Zhou, Ya-Chun Li, Jing Guo, Bo Nie, Yu-Ning Liu, Wei-Jing Liu.

BACKGROUND: Diabetic kidney disease (DKD) continues to pose a substantial public health challenge, in which cellular senescence is recognized as a pivotal driver of disease progression. While formononetin (FN) has been documented to exhibit anti-senescence properties, its potential as a therapeutic agent for DKD and the molecular mechanisms involved remain unexplored.
AIM: To evaluate the efficacy of FN using an in vitro model of high glucose (HG)-induced injury in MPC-5 podocytes. Transcriptomic profiling was employed to assess the influence of FN on global gene expression and to identify key signaling pathways affected by FN treatment. Furthermore, we sought to investigate the anti-senescence effects of FN and its regulatory role in the p53 signaling pathway in vitro.
METHODS: To elucidate the functional role of MDM2 in the anti-senescence mechanism of FN, MDM2 expression was silenced in MPC-5 cells using gene-specific knockdown. Finally, a mouse model of DKD was generated by combining a high-fat diet with intraperitoneal streptozotocin injections, and the therapeutic as well as anti-senescence effects of FN were evaluated in vivo.
RESULTS: In the HG-induced MPC-5 cell model, FN treatment significantly enhanced cell viability and reduced the secretion of senescence-associated secretory phenotype (SASP) factors in the supernatant. Transcriptomic analysis revealed the p53 signaling pathway as a central target of FN under HG conditions. FN treatment markedly suppressed β-galactosidase (β-GAL) activity, upregulated the expression of MDM2 and CCND1, downregulated the expression of p53 and p21, and inhibited p53 transcriptional activity in MPC-5 cells. These protective effects were abrogated upon MDM2 silencing. In DKD mice, FN administration improved renal function, alleviated histopathological damage, reduced renal SASP levels and β-GAL activity, and normalized the expression of key proteins in the p53 pathway.
CONCLUSION: Our findings demonstrate that FN confers significant therapeutic benefits against DKD in both cellular and animal models. The mechanism underlying these benefits involves the delay of cellular senescence through suppression of the p53 signaling pathway.

Keywords: Cellular senescence; Diabetic kidney disease; Formononetin; Transcriptomics; p53 signaling pathway

DOI: https://doi.org/10.4239/wjd.v17.i2.112500

Bioorg Chem. 2026 Feb 07. pii: S0045-2068(26)00150-1. [Epub ahead of print]173 109614

Bioactive treatments against chronic myeloid leukemia from Hypericum lancasteri targeting p53 pathway.

Xi-Ying Yang, Hong-Mei Li, Ying Zhou, Pan-Pan Zhang, Jia-Ping Zhou, Rui Dai, Ting-Ting Feng, Xing-Zhi Yang, Hua-Bin Wang, Ying Zhou, Xin Wei.

Keywords: Anti-tumor; Chronic myeloid leukemia; Hypericum lancasteri; MDM2; p53 targeting agents

DOI: https://doi.org/10.1016/j.bioorg.2026.109614

Curr Org Synth. 2025 ;22(8): 921-928

The Conjugation of Paclitaxel with Chalcones for Enhancing Anti-tumor Activity.

Zurong Song, Tianchen Wu.

INTRODUCTION: The decreased anticancer activity of paclitaxel was associated with many factors. The inactivity of p53 was one of the important causes. Some chalcones and their derivatives were found to inhibit the MDM2-p53 interaction. Therefore, the conjugation of chalcones with paclitaxel might be an effective strategy for enhancing the antitumor activity of paclitaxel.
METHODS: Here, three novel chalones, compounds 1a, 1b, and 1c were first designed and synthesized, followed by the conjugation of them with paclitaxel to prepare compounds 2a, 2b, and 2c. The anti-tumor activity of the aforementioned three novel paclitaxel-chalcone conjugates was evaluated by the MTT method, mitochondrial membrane potential analysis, apoptosis assay, and molecular docking.
RESULTS: The MTT assay demonstrated that compound 2a exhibited superior cytotoxicity compared to 2b and 2c toward breast cancer MCF-7 cells and MDA-MB-231 cells, with the differential activity correlating with electronic effects of their chalcone substituents: compound 2a possessed two electron-withdrawing chlorine groups, compound 2b lacked substitution, and compound 2c featured an electron-donating morpholine. Compared to paclitaxel, compound 2a exhibited a 1.7-fold enhancement in cytotoxic activity against MCF-7 cells and a 2.5-fold increase in potency against MDA-MB-231 cells. Further investigation showed that compound 2a could effectively decrease the mitochondrial membrane potential and induce cell apoptosis. Computational docking studies showed compound 2a formed two hydrogen bonds and one π-H interaction with MDM2, with a docking score of -8.5317.
DISCUSSION: Research findings demonstrate that the designed chalcone derivatives can effectively inhibit MDM2 activity, with the inhibitory potency closely associated with the substituents on the chalcone core. Notably, the introduction of chlorine substituents not only enhances the binding affinity to MDM2 but also improves the antitumor activity of its hybrid with paclitaxel. Molecular docking analysis reveals that the chlorine-substituted chalcone forms a π-H interaction with Gln72 of MDM2, a feature absent in the other two designed chalcone structures. Furthermore, the chlorine substituent may increase the lipophilicity of the hybrid, facilitating cellular uptake and thereby potentiating its anticancer efficacy.
CONCLUSION: These findings indicated that the conjugation of paclitaxel with chalones might be an effective strategy for strengthening the anticancer activity of paclitaxel.

Keywords: Paclitaxel; anticancer; activity.; chalone; conjugate; synthesis

DOI: https://doi.org/10.2174/0115701794395003250725111929