Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton’s Tyrosine Kinase Inhibitor in Early Clinical Development

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.