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Rational discovery of dual-indication multi-target PDE/Kinase inhibitor for precision anti-cancer therapy using structural systems pharmacology.

TitleRational discovery of dual-indication multi-target PDE/Kinase inhibitor for precision anti-cancer therapy using structural systems pharmacology.
Publication TypeJournal Article
Year of Publication2019
AuthorsLim H, He D, Qiu Y, Krawczuk P, Sun X, Xie L
JournalPLoS Comput Biol
Date Published2019 06
KeywordsAntineoplastic Agents, Computational Biology, Drug Discovery, Humans, Pharmacogenetics, Phosphodiesterase Inhibitors, Precision Medicine

Many complex diseases such as cancer are associated with multiple pathological manifestations. Moreover, the therapeutics for their treatments often lead to serious side effects. Thus, it is needed to develop multi-indication therapeutics that can simultaneously target multiple clinical indications of interest and mitigate the side effects. However, conventional one-drug-one-gene drug discovery paradigm and emerging polypharmacology approach rarely tackle the challenge of multi-indication drug design. For the first time, we propose a one-drug-multi-target-multi-indication strategy. We develop a novel structural systems pharmacology platform 3D-REMAP that uses ligand binding site comparison and protein-ligand docking to augment sparse chemical genomics data for the machine learning model of genome-scale chemical-protein interaction prediction. Experimentally validated predictions systematically show that 3D-REMAP outperforms state-of-the-art ligand-based, receptor-based, and machine learning methods alone. As a proof-of-concept, we utilize the concept of drug repurposing that is enabled by 3D-REMAP to design dual-indication anti-cancer therapy. The repurposed drug can demonstrate anti-cancer activity for cancers that do not have effective treatment as well as reduce the risk of heart failure that is associated with all types of existing anti-cancer therapies. We predict that levosimendan, a PDE inhibitor for heart failure, inhibits serine/threonine-protein kinase RIOK1 and other kinases. Subsequent experiments and systems biology analyses confirm this prediction, and suggest that levosimendan is active against multiple cancers, notably lymphoma, through the direct inhibition of RIOK1 and RNA processing pathway. We further develop machine learning models to predict cancer cell-line's and a patient's response to levosimendan. Our findings suggest that levosimendan can be a promising novel lead compound for the development of safe, effective, and precision multi-indication anti-cancer therapy. This study demonstrates the potential of structural systems pharmacology in designing polypharmacology for precision medicine. It may facilitate transforming the conventional one-drug-one-gene-one-disease drug discovery process and single-indication polypharmacology approach into a new one-drug-multi-target-multi-indication paradigm for complex diseases.

Alternate JournalPLoS Comput. Biol.
PubMed ID31206508
PubMed Central IDPMC6576746
Grant ListR01 GM122845 / GM / NIGMS NIH HHS / United States
R01 LM011986 / LM / NLM NIH HHS / United States