Novel pathway compendium analysis elucidates mechanism of pro-angiogenic synthetic small molecule.
BACKGROUND
Computational techniques have been applied to experimental datasets to identify drug mode-of-action. A shortcoming of existing approaches is the requirement of large reference databases of compound expression profiles. Here, we developed a new pathway-based compendium analysis that couples multi-timepoint, controlled microarray data for a single compound with systems-based network analysis to elucidate drug mechanism more efficiently.


RESULTS
We applied this approach to a transcriptional regulatory footprint of phthalimide neovascular factor 1 (PNF1)-a novel synthetic small molecule that exhibits significant in vitro endothelial potency-spanning 1-48 h post-supplementation in human micro-vascular endothelial cells (HMVEC) to comprehensively interrogate PNF1 effects. We concluded that PNF1 first induces tumor necrosis factor-alpha (TNF-alpha) signaling pathway function which in turn affects transforming growth factor-beta (TGF-beta) signaling. These results are consistent with our previous observations of PNF1-directed TGF-beta signaling at 24 h, including differential regulation of TGF-beta-induced matrix metalloproteinase 14 (MMP14/MT1-MMP) which is implicated in angiogenesis. Ultimately, we illustrate how our pathway-based compendium analysis more efficiently generates hypotheses for compound mechanism than existing techniques.
Wieghaus
Kristen A
KA
Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
Gianchandani
Erwin P
EP
Paige
Mikell A
MA
Brown
Milton L
ML
Botchwey
Edward A
EA
Papin
Jason A
JA
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D007211:Indoles; C513698:SC-3-149; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D053511:Matrix Metalloproteinase 14