Evaluating Angiogenic Potential of Small Molecules Using Genetic Network Approaches
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40883_2018_Article_77.pdf
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Author(s)
Das, Anusuya
Merrill, Parker
Turner, Thomas
Paige, Mikell
Capitosti, Scott
Brown, Milton
Freshcorn, Brandon
Sok, Mary C P
Song, Hannah
Botchwey, Edward A
Date Issued
September 2018
Journal
Regenerative Engineering and Translational Medicine
Publisher
Springer International Publishing
Citation
Das, Anusuya et al. “Evaluating Angiogenic Potential of Small Molecules Using Genetic Network Approaches.” Regenerative Engineering and Translational Medicine (September 2018): 1-12 © 2018 The Author(s)
Version
Final published version
Abstract
Control of microvascular network growth is critical to treatment of ischemic tissue diseases and enhancing regenerative capacity of tissue engineering implants. Conventional therapeutic strategies for inducing angiogenesis aim to deliver one or more pro-angiogenic cytokines or to over-express known pro-angiogenic genes, but seldom address potential compensatory or cooperative effects between signals and the overarching signaling pathways that determine successful outcomes. An emerging grand challenge is harnessing the expanding knowledge base of angiogenic signaling pathways toward development of successful new therapies. We previously performed drug optimization studies by various substitutions of a 2-(2,6-dioxo-3-piperidyl)isoindole-1,3-dione scaffold to discover novel bioactive small molecules capable of inducing growth of microvascular networks, the most potent of which we termed phthalimide neovascularization factor 1 (PNF1, formerly known as SC-3-149). We then showed that PNF-1 regulates the transcription of signaling molecules that are associated with vascular initiation and maturation in a time-dependent manner through a novel pathway compendium analysis in which transcriptional regulatory networks of PNF-1-stimulated microvascular endothelial cells are overlaid with literature-derived angiogenic pathways. In this study, we generated three analogues (SC-3-143, SC-3-263, SC-3-13) through systematic transformations to PNF1 to evaluate the effects of electronic, steric, chiral, and hydrogen bonding changes on angiogenic signaling. We then expanded our compendium analysis toward these new compounds. Variables obtained from the compendium analysis were then used to construct a PLSR model to predict endothelial cell proliferation. Our combined approach suggests mechanisms of action involving suppression of VEGF pathways through TGF-β and NR3C1 network activation. Keywords: PNF-1; Pathway compendium analysis; Phthalimide compounds
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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DOI of Published Version
https://doi.org/10.1007/s40883-018-0077-8
