title: Heterotaxin: a TGF-β signaling inhibitor identified in a multi-phenotype profiling screen in Xenopus embryos.
abstract: Disruptions of anatomical left-right asymmetry result in life-threatening heterotaxic birth defects in vital organs. We performed a small molecule screen for left-right asymmetry phenotypes in Xenopus embryos and discovered a pyridine analog, heterotaxin, which disrupts both cardiovascular and digestive organ laterality and inhibits TGF-β-dependent left-right asymmetric gene expression. Heterotaxin analogs also perturb vascular development, melanogenesis, cell migration, and adhesion, and indirectly inhibit the phosphorylation of an intracellular mediator of TGF-β signaling. This combined phenotypic profile identifies these compounds as a class of TGF-β signaling inhibitors. Notably, heterotaxin analogs also possess highly desirable antitumor properties, inhibiting epithelial-mesenchymal transition, angiogenesis, and tumor cell proliferation in mammalian systems. Our results suggest that assessing multiple organ, tissue, cellular, and molecular parameters in a whole organism context is a valuable strategy for identifying the mechanism of action of bioactive compounds.
authors.affiliation: Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Dush
authors.forename: Andrew L
authors.initials: AL
authors.lastname: McIver
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Parr
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Young
authors.forename: Julie
authors.initials: J
authors.lastname: Fisher
authors.forename: Donna R
authors.initials: DR
authors.lastname: Newman
authors.forename: Philip L
authors.initials: PL
authors.lastname: Sannes
authors.forename: Marlene L
authors.initials: ML
authors.lastname: Hauck
authors.forename: Alexander
authors.initials: A
authors.lastname: Deiters
authors.forename: Nanette
authors.initials: N
authors.lastname: Nascone-Yoder
mesh_terms: D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010641:Phenotype; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D011725:Pyridines; D016212:Transforming Growth Factor beta; C558637:heterotaxin