Targeted therapies that suppress B cell receptor (BCR) signaling have emerged as promising agents in autoimmune disease and B cell malignancies. Bruton's tyrosine kinase (Btk) plays a crucial role in B cell development and activation through the BCR signaling pathway and represents a new target for diseases characterized by inappropriate B cell activity. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide (CC-292) is a highly selective, covalent Btk inhibitor and a sensitive and quantitative assay that measures CC-292-Btk engagement has been developed. This translational pharmacodynamic assay has accompanied CC-292 through each step of drug discovery and development. These studies demonstrate the quantity of Btk bound by CC-292 correlates with the efficacy of CC-292 in vitro and in the collagen-induced arthritis model of autoimmune disease. Recently, CC-292 has entered human clinical trials with a trial design that has provided rapid insight into safety, pharmacokinetics, and pharmacodynamics. This first-in-human healthy volunteer trial has demonstrated that a single oral dose of 2 mg/kg CC-292 consistently engaged all circulating Btk protein and provides the basis for rational dose selection in future clinical trials. This targeted covalent drug design approach has enabled the discovery and early clinical development of CC-292 and has provided support for Btk as a valuable drug target for B-cell mediated disorders.
Patients with non-small cell lung carcinoma (NSCLC) with activating mutations in epidermal growth factor receptor (EGFR) initially respond well to the EGFR inhibitors erlotinib and gefitinib. However, all patients relapse because of the emergence of drug-resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. Second-generation irreversible EGFR inhibitors are effective against T790M mutations in vitro, but retain affinity for wild-type EGFR (EGFR WT
Substituted cyclic ethers are commonly encountered structural subunits in a variety of natural products, such as ionophore antibiotics and marine toxins. The tetrahydrofuran unit is among the most ubiquitous of the naturally occurring cyclic ethers, and a number of elegant approaches to this ring system have been described in recent years.2 We report here a new approach to substituted tetrahydrofurans using a tandem oxonium ylide generation/Stevens [1,2]-shift protocol.The [l,2]-shift of ylides has received periodic attention with regard to mechanistic issues3 but has rarely been applied as a synthetic method. Since this reaction results
Fused bicyclic oxonium ylides, generated with catalytic Rh,(OAc), from cyclic ethers bearing pendant diazo ketones, undergo a [I ,2]or [2,3]-shift to give 0-bridged seven-or eight-membered carbocycles, in several cases with a high degree of stereoselectivity.
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