RT Journal Article
SR Electronic
T1 Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 219
OP 228
DO 10.1124/jpet.113.203489
VO 346
IS 2
A1 Erica K. Evans
A1 Richland Tester
A1 Sharon Aslanian
A1 Russell Karp
A1 Michael Sheets
A1 Matthew T. Labenski
A1 Steven R. Witowski
A1 Heather Lounsbury
A1 Prasoon Chaturvedi
A1 Hormoz Mazdiyasni
A1 Zhendong Zhu
A1 Mariana Nacht
A1 Martin I. Freed
A1 Russell C. Petter
A1 Alex Dubrovskiy
A1 Juswinder Singh
A1 William F. Westlin
YR 2013
UL http://jpet.aspetjournals.org/content/346/2/219.abstract
AB 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.