Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension.
Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension.
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DOI：
10.1126/sciadv.abh3794
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发表时间：
2021-10-22
期刊：
影响因子：
13.6
通讯作者：
Chan SY
中科院分区：
文献类型：
--
作者：
Negi V;Yang J;Speyer G;Pulgarin A;Handen A;Zhao J;Tai YY;Tang Y;Culley MK;Yu Q;Forsythe P;Gorelova A;Watson AM;Al Aaraj Y;Satoh T;Sharifi-Sanjani M;Rajaratnam A;Sembrat J;Provencher S;Yin X;Vargas SO;Rojas M;Bonnet S;Torrino S;Wagner BK;Schreiber SL;Dai M;Bertero T;Al Ghouleh I;Kim S;Chan SY
生成了一个网络依赖性平台，以定义肺动脉高压中癌症药物机制的景观。癌症疗法正在考虑用于治疗罕见的非癌性疾病，如肺动脉高压（PH），但缺乏有效的计算筛选。通过利用癌症和PH之间的相似性的转录组学差异依赖性分析，我们绘制了依赖于PH基因簇重新布线的癌症药物功能的景观。预测溴结构域和额外末端基序（BET）蛋白抑制剂依赖于包括半乳糖凝集素-8（LGALS 8）在内的几个基因簇。相应地，发现LGALS 8介导BET抑制剂依赖性的内皮细胞凋亡控制，这是体内PH的重要作用。另外，胡椒类似物的行动预计取决于铁硫生物合成基因ISCU。相应地，类似物被发现抑制ISCU谷胱甘肽化，挽救氧化代谢，减少内皮细胞凋亡，提高PH。因此，我们确定了关键的药物基因轴中央内皮功能障碍和治疗优先级PH。这些结果建立了一个广泛的，网络依赖性平台，重新定义癌症药物用于非癌性疾病。
A network dependency platform was generated to define a landscape of cancer drug mechanisms in pulmonary hypertension. Cancer therapies are being considered for treating rare noncancerous diseases like pulmonary hypertension (PH), but effective computational screening is lacking. Via transcriptomic differential dependency analyses leveraging parallels between cancer and PH, we mapped a landscape of cancer drug functions dependent upon rewiring of PH gene clusters. Bromodomain and extra-terminal motif (BET) protein inhibitors were predicted to rely upon several gene clusters inclusive of galectin-8 (LGALS8). Correspondingly, LGALS8 was found to mediate the BET inhibitor–dependent control of endothelial apoptosis, an essential role for PH in vivo. Separately, a piperlongumine analog’s actions were predicted to depend upon the iron-sulfur biogenesis gene ISCU. Correspondingly, the analog was found to inhibit ISCU glutathionylation, rescuing oxidative metabolism, decreasing endothelial apoptosis, and improving PH. Thus, we identified crucial drug-gene axes central to endothelial dysfunction and therapeutic priorities for PH. These results establish a wide-ranging, network dependency platform to redefine cancer drugs for use in noncancerous conditions.
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影响因子：
16.6
作者：
Cheng F;Desai RJ;Handy DE;Wang R;Schneeweiss S;Barabási AL;Loscalzo J
通讯作者：
Loscalzo J
影响因子：
5.4
作者：
Dudley, Andrew C.
通讯作者：
Dudley, Andrew C.
影响因子：
64.8
作者：
Gordon, David E.;Jang, Gwendolyn M.;Krogan, Nevan J.
通讯作者：
Krogan, Nevan J.
DOI：
10.1164/rccm.201809-1737oc
发表时间：
2019-06-15
影响因子：
24.7
作者：
Crnkovic, Slaven;Egemnazarov, Bakytbek;Kwapiszewska, Grazyna
通讯作者：
Kwapiszewska, Grazyna
影响因子：
14.9
作者：
Jung S;Kim S
通讯作者：
Kim S