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

被引：197

作者：

Crawford, James J. y ^{[1
]}

Johnson, Adam R. ^{[1
]}

Misner, Dinah L. ^{[1
,2
]}

Belmont, Lisa D. ^{[1
]}

Castanedo, Georgette ^{[1
]}

Choy, Regina ^{[1
]}

Coraggio, Melis ^{[1
,3
]}

Doug, Liming ^{[1
]}

Eigenbrot, Charles ^{[1
]}

Erickson, Rebecca ^{[1
]}

Ghilardi, Nico ^{[1
]}

Hau, Jonathan ^{[1
]}

Katewa, Arna ^{[1
]}

Kohli, Pawan Bir ^{[1
]}

Lee, Wendy ^{[1
]}

Lubach, Joseph W. ^{[1
]}

McKenzie, Brent S. ^{[1
]}

Ortwine, Daniel F. ^{[1
]}

Schutt, Leah ^{[1
]}

Tay, Suzanne ^{[1
]}

Wei, BinQing ^{[1
]}

Reif, Karin ^{[1
]}

Liu, Lichuan ^{[1
]}

Wong, Harvey ^{[1
,4
]}

Young, Wendy B. ^{[1
]}

机构：

[1] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA

[2] Alios BioPharma Inc, 260 East Grand Ave, San Francisco, CA 94080 USA

[3] US FDA, 10903 New Hampshire Ave, Silver Spring, MD 20903 USA

[4] Univ British Columbia, Fac Pharmaceut Sci, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 06期

关键词：

B-CELL MALIGNANCIES; CHRONIC LYMPHOCYTIC-LEUKEMIA; BTK INHIBITOR; MEDIATED GLOMERULONEPHRITIS; IRREVERSIBLE INHIBITORS; INFLAMMATORY DISEASES; TARGETING BTK; MURINE LUPUS; DRUG DESIGN; IBRUTINIB;

D O I：

10.1021/acs.jmedchem.7b01712

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic tyrosine kinase involved in B-cell and myeloid cell activation, downstream of B-cell and Fc gamma 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.

引用

页码：2227 / 2245

页数：19

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