2. Academic Validation
  3. Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development

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

  • J Med Chem. 2018 Mar 22;61(6):2227-2245. doi: 10.1021/acs.jmedchem.7b01712.
James J Crawford 1,  Adam R Johnson 1,  Dinah L Misner 1,  Lisa D Belmont 1,  Georgette Castanedo 1,  Regina Choy 1,  Melis Coraggio 1,  Liming Dong 1,  Charles Eigenbrot 1,  Rebecca Erickson 1,  Nico Ghilardi 1,  Jonathan Hau 1,  Arna Katewa 1,  Pawan Bir Kohli 1,  Wendy Lee 1,  Joseph W Lubach 1,  Brent S McKenzie 1,  Daniel F Ortwine 1,  Leah Schutt 1,  Suzanne Tay 1,  BinQing Wei 1,  Karin Reif 1,  Lichuan Liu 1,  Harvey Wong 1,  Wendy B Young 1
Affiliations

Affiliation

  • 1 Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
PMID: 29457982 DOI: 10.1021/acs.jmedchem.7b01712
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-19834
    99.42%, Btk Inhibitor
    Btk