Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for XXXX .

@entity808 @entity1 @entity5513 @entity137 @entity5 @entity70281 @entity19 @entity1994 @entity4357
OBJECTIVES/HYPOTHESIS: Recent studies indicate that @entity5513 ( @entity5513 ) rely on @entity4357 3-kinase/ @entity1994 activation to promote cell proliferation and survival; therefore, targeting @entity1994 may provide new therapeutic options. We have previously shown that AR42, a novel histone deacetylase inhibitor, potently suppresses VS growth in vitro at doses correlating with @entity1994 inactivation. The objectives of the current study were translational: 1) to examine the end biologic effects of AR42 on @entity5 growth in vivo, 2) to validate @entity1994 as its in vivo molecular target, 3) to determine whether AR42 penetrates the @entity70281 ) to study the pharmacotoxicity profile of AR42. STUDY DESIGN: In vivo @entity19 studies. METHODS: AR42 was dosed orally in @entity19 @entity808 allografts and @entity1 VS xenografts. Magnetic resonance imaging was used to quantify changes in @entity5 volume, and intracellular molecular targets were analyzed using immunohistochemistry. @entity70281 penetration was assayed, and both blood-chemistry measurements and histology studies were used to evaluate @entity137 . RESULTS: Growth of @entity808 implants was dramatically decreased by AR42 at doses correlating with @entity1994 dephosphorylation, cell cycle arrest, and apoptosis. AR42 penetrated the @entity70281 , and wild-type @entity19 fed AR42 for 6 months behaved normally and gained weight appropriately. Blood-chemistry studies and organ histology performed after 3 and 6 months of AR42 treatment demonstrated no clinically significant abnormalities. CONCLUSIONS: AR42 suppresses @entity808 growth at doses correlating with @entity1994 pathway inhibition. This orally bioavailable drug penetrates the @entity70281 , is well tolerated, and represents a novel candidate for translation to @entity1 VS clinical trials.
