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

Abstract

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.

Efficacy and Pharmacodynamic Modeling of the BTK Inhibitor Evobrutinib in Autoimmune Disease Models

“…However, protection is lost when only the kinase domain is mutated (67). A recent publication shows efficacy of GDC-0853, a reversible BTK inhibitor with high selectivity that does not hit BMX, in the rat CIA model (68).…”

Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia

“…GDC-0853 is an oral, highly selective and reversible BTK inhibitor which binds independently from C481 [112,113]. GDC-0853 suppresses downstream BCR signaling, resulting in downregulation of the NF-κB pathway and inhibition of cell proliferation [112,113]. In a phase I study, GDC-0853 was indicated in 24 patients with relapsed or refractory non-Hodgkin lymphoma (10 patients) or CLL (14 patients) [114].…”

Absence of Pharmacokinetic Interactions between the Bruton’s Tyrosine Kinase Inhibitor Fenebrutinib and Methotrexate

“…GDC-0853 (fenebrutinib) is a highly selective, reversible inhibitor of BTK and is being developed by Genentech as an orally administered treatment of patients with RA, systemic lupus erythematosus, and chronic spontaneous urticaria. Unlike other first-generation BTK inhibitors that act upon several different tyrosine kinases, fenebrutinib binds noncovalently to BTK in an orientation that enables greater selectivity (Crawford et al, 2018). The in vitro cellular potency of fenebrutinib was determined to be 11 nM for the inhibition of BTK autophosphorylation in human whole blood obtained from healthy subjects.…”