Pan-transcriptome-based candidate therapeutic discovery for idiopathic pulmonary fibrosis.
Pan-transcriptome-based candidate therapeutic discovery for idiopathic pulmonary fibrosis.
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DOI：
10.1177/1753466620971143
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发表时间：
2020-01
影响因子：
4.3
通讯作者：
Jegga AG
中科院分区：
文献类型：
--
作者：
Wang Y;Yella JK;Ghandikota S;Cherukuri TC;Ediga HH;Madala SK;Jegga AG
There are two US Food and Drug Administration (FDA)-approved drugs, pirfenidone and nintedanib, for treatment of patients with idiopathic pulmonary fibrosis (IPF). However, neither of these drugs provide a cure. In addition, both are associated with several drug-related adverse events. Hence, the pursuit for newer IPF therapeutics continues. Recent studies show that joint analysis of systems-biology-level information with drug–disease connectivity are effective in discovery of biologically relevant candidate therapeutics. Publicly available gene expression signatures from patients with IPF were used to query a large-scale perturbagen signature library to discover compounds that can potentially reverse dysregulated gene expression in IPF. Two methods were used to calculate IPF–compound connectivity: gene expression-based connectivity and feature-based connectivity. Identified compounds were further prioritized if their shared mechanism(s) of action were IPF-related. We found 77 compounds as potential candidate therapeutics for IPF. Of these, 39 compounds are either FDA-approved for other diseases or are currently in phase II/III clinical trials suggesting their repurposing potential for IPF. Among these compounds are multiple receptor kinase inhibitors (e.g. nintedanib, currently approved for IPF, and sunitinib), aurora kinase inhibitor (barasertib), epidermal growth factor receptor inhibitors (erlotinib, gefitinib), calcium channel blocker (verapamil), phosphodiesterase inhibitors (roflumilast, sildenafil), PPAR agonists (pioglitazone), histone deacetylase inhibitors (entinostat), and opioid receptor antagonists (nalbuphine). As a proof of concept, we performed in vitro validations with verapamil using lung fibroblasts from IPF and show its potential benefits in pulmonary fibrosis. As about half of the candidates discovered in this study are either FDA-approved or are currently in clinical trials for other diseases, rapid translation of these compounds as potential IPF therapeutics is possible. Further, the integrative connectivity analysis framework in this study can be adapted in early phase drug discovery for other common and rare diseases with transcriptomic profiles. The reviews of this paper are available via the supplemental material section.
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影响因子：
6.1
作者：
Han AC;Deng JX;Huang QS;Zheng HY;Zhou P;Liu ZW;Chen ZB
通讯作者：
Chen ZB
影响因子：
64.5
作者：
Lamb, J;Ramaswamy, S;Ewen, ME
通讯作者：
Ewen, ME
影响因子：
158.5
作者：
Kolb, Martin;Raghu, Ganesh;Martinez, Fernando J.
通讯作者：
Martinez, Fernando J.
影响因子：
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作者：
Hsu, Eileen;Shi, Haiwen;Jordan, Rick M.;Lyons-Weiler, James;Pilewski, Joseph M.;Feghali-Bostwick, Carol A.
通讯作者：
Feghali-Bostwick, Carol A.
影响因子：
14.9
作者：
Chen J;Bardes EE;Aronow BJ;Jegga AG
通讯作者：
Jegga AG