1206248-85-2Relevant articles and documents
HETEROARYL AMIDES USEFUL AS KIF18A INHIBITORS
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Paragraph 0192-0194, (2020/07/14)
The present invention relates to chemical compounds having a general formula (I), as defined herein, and synthetic intermediates thereof, which are capable of modulating KIF18A protein thereby influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of KIF18A.
Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development
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.
supporting information, p. 2227 - 2245 (2018/03/26)
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.