MOTIVATION: 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.
MOTIVATION: 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.
Authors: Justin Lamb; Emily D Crawford; David Peck; Joshua W Modell; Irene C Blat; Matthew J Wrobel; Jim Lerner; Jean-Philippe Brunet; Aravind Subramanian; Kenneth N Ross; Michael Reich; Haley Hieronymus; Guo Wei; Scott A Armstrong; Stephen J Haggarty; Paul A Clemons; Ru Wei; Steven A Carr; Eric S Lander; Todd R Golub Journal: Science Date: 2006-09-29 Impact factor: 47.728
Authors: Kristen A Wieghaus; Meghan M Nickerson; Caren E Petrie Aronin; Lauren S Sefcik; Richard J Price; Mikell A Paige; Milton L Brown; Edward A Botchwey Journal: Biomaterials Date: 2008-09-18 Impact factor: 12.479
Authors: Kristen A Wieghaus; Erwin P Gianchandani; Rebekah A Neal; Mikell A Paige; Milton L Brown; Jason A Papin; Edward A Botchwey Journal: Biotechnol Bioeng Date: 2009-07-01 Impact factor: 4.530
Authors: Kristen A Wieghaus; Meghan M Nickerson; Caren E Petrie Aronin; Lauren S Sefcik; Richard J Price; Mikell A Paige; Milton L Brown; Edward A Botchwey Journal: Biomaterials Date: 2008-09-18 Impact factor: 12.479
Authors: Kristen A Wieghaus; Erwin P Gianchandani; Rebekah A Neal; Mikell A Paige; Milton L Brown; Jason A Papin; Edward A Botchwey Journal: Biotechnol Bioeng Date: 2009-07-01 Impact factor: 4.530