RNA-Mediated Mechanisms of Disease Group, Department of Clinical and Biomedical Sciences (Medical School), Faculty of Health and Life Sciences, University of Exeter, Exeter EX2 5DW, UK.
Cells. 2024 Mar 15;13(6):517. doi: 10.3390/cells13060517.
Repurposing previously approved drugs may fast track the route to the clinic for potential senotherapeutics and improves the inefficiency of the clinical drug development pipeline. We performed a repurposing screen of 240 clinically approved molecules in human primary dermal fibroblasts for their effects on expression. Molecules demonstrating effects on expression underwent secondary screening for senescence-associated beta galactosidase (SAB) activity, based on effect size, direction, and/or molecule identity. Selected molecules then underwent a more detailed assessment of senescence phenotypes including proliferation, apoptosis, DNA damage, senescence-associated secretory phenotype (SASP) expression, and regulators of alternative splicing. A selection of the molecules demonstrating effects on senescence were then used in a new bioinformatic structure-function screen to identify common structural motifs. In total, 90 molecules displayed altered expression at one or other dose, of which 15 also displayed effects on SAB positivity in primary human dermal fibroblasts. Of these, 3 were associated with increased SAB activity, and 11 with reduced activity. The female synthetic sex hormones-diethylstilboestrol, ethynyl estradiol and levonorgestrel-were all associated with a reduction in aspects of the senescence phenotype in male cells, with no effects visible in female cells. Finally, we identified that the 30 compounds that decreased activity the most had a common substructure linked to this function. Our results suggest that several drugs licensed for other indications may warrant exploration as future senotherapies, but that different donors and potentially different sexes may respond differently to senotherapeutic compounds. This underlines the importance of considering donor-related characteristics when designing drug screening platforms.
重新利用先前批准的药物可能会加快潜在衰老治疗药物进入临床的速度，并提高临床药物开发管道的效率。我们在人原代真皮成纤维细胞中对 240 种临床批准的分子进行了重新利用筛选，以研究它们对 表达的影响。对 表达有影响的分子根据效应大小、方向和/或分子身份，进行衰老相关β半乳糖苷酶（SAB）活性的二次筛选。然后，选择的分子会进行更详细的衰老表型评估，包括增殖、凋亡、DNA 损伤、衰老相关分泌表型（SASP）表达和选择性剪接调节剂。一些显示出对衰老有影响的分子随后被用于新的生物信息学结构-功能筛选，以识别常见的结构基序。总共 90 种分子在一个或另一个剂量下显示出 表达改变，其中 15 种分子也显示出对原代人真皮成纤维细胞中 SAB 阳性的影响。其中，3 种与 SAB 活性增加有关，11 种与活性降低有关。女性合成性激素-己烯雌酚、乙炔雌二醇和左炔诺孕酮-都与男性细胞衰老表型的某些方面减少有关，而在女性细胞中没有可见的影响。最后，我们发现降低 活性最多的 30 种化合物具有与该功能相关的共同亚结构。我们的结果表明，几种被许可用于其他适应症的药物可能需要作为未来的衰老治疗药物进行探索，但不同的供体和潜在的不同性别可能对衰老治疗化合物有不同的反应。这强调了在设计药物筛选平台时考虑供体相关特征的重要性。
