Structure-Guided Blockade of XXXX Kinase in @entity2967 .

@entity1 @entity390 @entity6827 @entity5 @entity6823 @entity4 @entity2967 @entity6824 @entity2342
BACKGROUND: Expression of the @entity6824 ( @entity6824 ) gene is elevated in most @entity2967 . This observation has led to the discovery and clinical development of therapy targeting the @entity6823 ( @entity6823 ). METHODS: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective @entity6823 inhibitor, @entity6827 , that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of @entity6827 that was administered orally in @entity1 with solid @entity5 (dose-escalation study). In the second part, we evaluated @entity6827 at the chosen phase 2 dose in an extension cohort of @entity1 with @entity2967 (extension study). Pharmacokinetic and @entity5 responses in the enrolled @entity1 were assessed, and @entity6824 in situ hybridization was performed to confirm the mechanism of action of @entity6827 and that the pattern of @entity6824 expression was consistent with the pathological features of @entity2967 . RESULTS: A total of 41 @entity1 were enrolled in the dose-escalation study, and an additional 23 @entity1 were enrolled in the extension study. The chosen phase 2 dose of @entity6827 was 1000 mg per day. In the extension study, 12 @entity1 with @entity2967 had a partial response and 7 @entity1 had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, @entity390 , @entity2342 , and periorbital @entity4 ; adverse events rarely led to discontinuation of treatment. CONCLUSIONS: Treatment of @entity2967 with @entity6827 resulted in a prolonged regression in @entity5 volume in most @entity1 . (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861.).
