- Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development
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Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fcγ receptors, respectively. Preclinical studies have indicated that inhibition of Btk activity might offer a potential therapy in autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Here we disclose the discovery and preclinical characterization of a potent, selective, and noncovalent Btk inhibitor currently in clinical development. GDC-0853 (29) suppresses B cell- and myeloid cell-mediated components of disease and demonstrates dose-dependent activity in an in vivo rat model of inflammatory arthritis. It demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria. On the basis of its potency, selectivity, long target residence time, and noncovalent mode of inhibition, 29 has the potential to be a best-in-class Btk inhibitor for a wide range of immunological indications.
- Crawford, James J.,Johnson, Adam R.,Misner, Dinah L.,Belmont, Lisa D.,Castanedo, Georgette,Choy, Regina,Coraggio, Melis,Dong, Liming,Eigenbrot, Charles,Erickson, Rebecca,Ghilardi, Nico,Hau, Jonathan,Katewa, Arna,Kohli, Pawan Bir,Lee, Wendy,Lubach, Joseph W.,McKenzie, Brent S.,Ortwine, Daniel F.,Schutt, Leah,Tay, Suzanne,Wei, Binqing,Reif, Karin,Liu, Lichuan,Wong, Harvey,Young, Wendy B.
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p. 2227 - 2245
(2018/03/26)
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- PYRIDONE AND AZA-PYRIDONE COMPOUNDS AND METHODS OF USE
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Pyridone and aza-pyridone compounds of Formula I are provided, including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for inhibiting Btk kinase, and for treating immune disorders such as inflammation mediated by Btk kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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