@entity5459 ( XXXX ) is an inhibitor of @entity8047 activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition.

@entity1 @entity72330 @entity8047 @entity5459 @entity5 @entity993 @entity13525 @entity817 @entity1366 @entity29343 @entity3903 @entity12363
PURPOSE: Despite their preclinical promise, previous @entity8047 inhibitors have shown little benefit for @entity1 . This likely reflects the narrow therapeutic window for @entity8047 inhibitors due to the essential role of the @entity3903 /44 MAPK pathway in many nontumor tissues. @entity5459 is a potent and selective allosteric inhibitor of the @entity12363 and @entity29343 ( @entity72330 ) enzymes with promising antitumor activity in a phase I clinical trial (ASCO 2010). Our studies characterize @entity5459 ' enzymatic, cellular, and in vivo activities, describing its unusually long circulating half-life. EXPERIMENTAL DESIGN: Enzymatic studies were conducted to determine @entity5459 inhibition of recombinant @entity8047 , following or preceding RAF kinase activation. Cellular studies examined @entity5459 inhibition of @entity1366 phosphorylation (p- @entity1366 ) as well as @entity72330 phosphorylation and activation. Further studies explored the sensitivity of @entity5 cell lines, and drug pharmacokinetics and efficacy in multiple @entity5 xenograft models. RESULTS: In enzymatic and cellular studies, @entity5459 inhibits @entity72330 kinase activity and prevents Raf-dependent @entity8047 phosphorylation (S217 for @entity12363 ), producing prolonged p- @entity1366 inhibition. Potent cell growth inhibition was evident in most @entity5 lines with mutant @entity817 or Ras. In xenografted @entity5 models, @entity5459 orally dosed once daily had a long circulating half-life and sustained suppression of p- @entity1366 for more than 24 hours; @entity5459 also reduced @entity5 Ki67, increased @entity993 ( @entity13525 / @entity13525 ), and caused @entity5 growth inhibition in multiple @entity5 models. The largest antitumor effect was among @entity5 harboring mutant @entity817 or Ras. CONCLUSIONS: @entity5459 combines high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clinical @entity8047 inhibitors.
