Open AccessConnecting Neuronal Cell Protective Pathways and Drug Combinations in a Huntington’s Disease Model through the Application of Quantitative Systems Pharmacology
Author(s) -
Fen Pei,
Hongchun Li,
Mark J. Henderson,
Steven A. Titus,
Ajit Jadhav,
Anton Simeonov,
Murat Can Çobanoğlu,
Seyed H. Mousavi,
Tongying Shun,
Lee A. McDermott,
Prema Iyer,
Michael Fioravanti,
Diane L. Carlisle,
Robert M. Friedlander,
İvet Bahar,
D Lansing Taylor,
Timothy R. Lezon,
Andrew M. Stern,
Mark E. Schurdak
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-17378-y
Subject(s) - huntington's disease , drug discovery , systems pharmacology , drug , small molecule , huntingtin , pharmacology , programmed cell death , computational biology , systems biology , biology , huntingtin protein , cell , mechanism of action , disease , neuroscience , chemistry , bioinformatics , in vitro , biochemistry , apoptosis , medicine , pathology
Quantitative Systems Pharmacology (QSP) is a drug discovery approach that integrates computational and experimental methods in an iterative way to gain a comprehensive, unbiased understanding of disease processes to inform effective therapeutic strategies. We report the implementation of QSP to Huntington’s Disease, with the application of a chemogenomics platform to identify strategies to protect neuronal cells from mutant huntingtin induced death. Using the ST Hdh Q111 cell model, we investigated the protective effects of small molecule probes having diverse canonical modes-of-action to infer pathways of neuronal cell protection connected to drug mechanism. Several mechanistically diverse protective probes were identified, most of which showed less than 50% efficacy. Specific combinations of these probes were synergistic in enhancing efficacy. Computational analysis of these probes revealed a convergence of pathways indicating activation of PKA. Analysis of phospho-PKA levels showed lower cytoplasmic levels in ST Hdh Q111 cells compared to wild type ST Hdh Q7 cells, and these levels were increased by several of the protective compounds. Pharmacological inhibition of PKA activity reduced protection supporting the hypothesis that protection may be working, in part, through activation of the PKA network. The systems-level studies described here can be broadly applied to any discovery strategy involving small molecule modulation of disease phenotype.