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Disruption of p53-MDM2/MDMX interaction by smaller inhibitors is a promising therapeutic intervention gaining tremendous interest. However, no MDM2/MDMX inhibitors have been marketed so far. Drug repurposing is a validated, practical approach to drug discovery. In this regard, we employed structure-based virtual screening in a reservoir of marketed drugs and identified nintedanib as a new MDM2/MDMX dual inhibitor. The computational structure analysis and biochemical experiments uncover that nintedanib binds MDM2/MDMX similarly to RO2443, a dual MDM2/MDMX inhibitor. Furthermore, the mechanistic study reveals that nintedanib disrupts the physical interaction of p53-MDM2/MDMX, enabling the transcriptional activation of p53 and the subsequent cell cycle arrest and growth inhibition in p53+/+ cancer cells. Lastly, structural minimisation of nintedanib yields H3 with the equivalent potency. In summary, this work provides a solid foundation for reshaping nintedanib as a valuable lead compound for the further design of MDM2/MDMX dual inhibitors. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to assess alterations in right ventricular (RV) function following percutaneous coronary intervention (PCI) in patients with chronic coronary syndromes utilizing three‐dimensional speckle tracking echocardiography (3D‐STE). Methods: A prospective study was conducted involving 136 patients diagnosed with chronic coronary syndromes undergoing PCI, constituting the study group, alongside 110 age‐ and gender‐matched healthy volunteers serving as the control group. Echocardiographic evaluations, including both conventional and three‐dimensional assessments, were performed on all study participants at 1‐week, 6, and 12 months post‐PCI. Parameters such as tricuspid annular plane systolic excursion (TAPSE) were derived from conventional echocardiography, while tricuspid lateral annular systolic velocity (S') was measured via tissue Doppler imaging. 3D‐STE was utilized to quantify metrics including right ventricular fractional area change (RVFAC), right ventricular free wall longitudinal strain (RVFWLS), right ventricular global longitudinal strain (RVGLS), right ventricular stroke volume (RVSV), and right ventricular ejection fraction (RVEF). Results: TAPSE, S', RVFAC, RVFWLS, RVGLS, RVSV, and RVEF exhibited significant increases from 1‐week to 6 months post‐PCI (p < 0.05). However, from 6 to 12 months post‐PCI, RVFAC, RVGLS, RVSV, and RVEF demonstrated no notable changes (p > 0.05). Meanwhile, TAPSE, S', and RVFWLS sustained significant elevations: TAPSE (19.63 ± 3.253% to 22.603 ± 2.885%, p < 0.001); S' (10.57 ± 2.643 to 12.61 ± 2.189 cm/s, p < 0.001); RVFWLS (18.64 ± 2.745% to 19.926 ± 3.291%, p = 0.002). At 12 months post‐PCI, S', RVFAC, RVGLS, RVSV, and RVEF remained lower than those of the healthy control group, but the differences were not statistically significant (p > 0.05). However, RVFWLS was significantly lower compared to the healthy control group (19.926 ± 3.291% vs. 22.10 ± 1.994%, p < 0.001). Conclusion: Following PCI, right ventricular systolic function in patients with chronic coronary syndromes improves significantly over time. However, even at the 12‐month post‐PCI mark, RVFWLS remains lower than that of the control group. Notably, 3D‐STE emerges as a noninvasive method for quantifying right ventricular systolic function post‐PCI in chronic coronary syndrome patients. [ABSTRACT FROM AUTHOR]