title: Induction of heart valve lesions by small-molecule ALK5 inhibitors.
abstract: Aberrant signaling by transforming growth factor-β (TGF-β) and its type I (ALK5) receptor has been implicated in a number of human diseases and this pathway is considered a potential target for therapeutic intervention. Transforming growth factor-β signaling via ALK5 plays a critical role during heart development, but the role of ALK5 in the adult heart is poorly understood. In the current study, the preclinical toxicology of ALK5 inhibitors from two different chemistry scaffolds was explored. Ten-week-old female Han Wistar rats received test compounds by the oral route for three to seven days. Both compounds induced histopathologic heart valve lesions characterized by hemorrhage, inflammation, degeneration, and proliferation of valvular interstitial cells. The pathology was observed in all animals, at all doses tested, and occurred in all four heart valves. Immunohistochemical analysis of ALK5 in rat hearts revealed expression in the valves, but not in the myocardium. Compared to control animals, protein levels of ALK5 were unchanged in the heart valves of treated animals. We also observed a physeal dysplasia in the femoro-tibial joint of rats treated with ALK5 inhibitors, a finding consistent with a pharmacological effect described previously with ALK5 inhibitors. Overall, these findings suggest that TGF-β signaling via ALK5 plays a critical role in maintaining heart valve integrity.
authors.affiliation: Department of General Toxicology Sciences, AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Anderton
authors.forename: Howard R
authors.initials: HR
authors.lastname: Mellor
authors.forename: Alex
authors.initials: A
authors.lastname: Bell
authors.forename: Claire
authors.initials: C
authors.lastname: Sadler
authors.forename: Martin
authors.initials: M
authors.lastname: Pass
authors.forename: Steve
authors.initials: S
authors.lastname: Powell
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Steele
authors.forename: Ruth R A
authors.initials: RR
authors.lastname: Roberts
authors.forename: Annabelle
authors.initials: A
authors.lastname: Heier
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004353:Drug Evaluation, Preclinical; D005260:Female; D006351:Heart Valves / Q000187:drug effects / Q000473:pathology*; D007150:Immunohistochemistry / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625843:Tgfbr1 protein, rat