title: Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans.
abstract: 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.
authors.affiliation: Celgene Avilomics Research, Bedford, MA 01730, USA.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Evans
authors.forename: Richland
authors.initials: R
authors.lastname: Tester
authors.forename: Sharon
authors.initials: S
authors.lastname: Aslanian
authors.forename: Russell
authors.initials: R
authors.lastname: Karp
authors.forename: Michael
authors.initials: M
authors.lastname: Sheets
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Labenski
authors.forename: Steven R
authors.initials: SR
authors.lastname: Witowski
authors.forename: Heather
authors.initials: H
authors.lastname: Lounsbury
authors.forename: Prasoon
authors.initials: P
authors.lastname: Chaturvedi
authors.forename: Hormoz
authors.initials: H
authors.lastname: Mazdiyasni
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Zhu
authors.forename: Mariana
authors.initials: M
authors.lastname: Nacht
authors.forename: Martin I
authors.initials: MI
authors.lastname: Freed
authors.forename: Russell C
authors.initials: RC
authors.lastname: Petter
authors.forename: Alex
authors.initials: A
authors.lastname: Dubrovskiy
authors.forename: Juswinder
authors.initials: J
authors.lastname: Singh
authors.forename: William F
authors.initials: WF
authors.lastname: Westlin
mesh_terms: D000178:Acrylamides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D004311:Double-Blind Method; D006801:Humans; D051379:Mice; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000178:Acrylamides; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; C583568:spebrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse