5VFI

Bruton's tyrosine kinase (BTK) with GDC-0853

Summary for 5VFI

• Entry DOI: 10.2210/pdb5vfi/pdb
• Descriptor: Tyrosine-protein kinase BTK, 2-[3'-(hydroxymethyl)-1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo[1,6-dihydro[3,4'-bipyridine]]-2'-yl]-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: protein kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: Q06187
• Total number of polymer chains: 1
• Total formula weight: 32951.75

Authors

Steinbacher, S.,Eigenbrot, C. (deposition date: 2017-04-07, release date: 2018-02-28, Last modification date: 2024-03-13)

Primary citation

Crawford, J.J.,Johnson, A.R.,Misner, D.L.,Belmont, L.D.,Castanedo, G.,Choy, R.,Coraggio, M.,Dong, L.,Eigenbrot, C.,Erickson, R.,Ghilardi, N.,Hau, J.,Katewa, A.,Kohli, P.B.,Lee, W.,Lubach, J.W.,McKenzie, B.S.,Ortwine, D.F.,Schutt, L.,Tay, S.,Wei, B.,Reif, K.,Liu, L.,Wong, H.,Young, W.B.
Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development.
J. Med. Chem., 61:2227-2245, 2018

PubMed 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.

PubMed: 29457982
DOI: 10.1021/acs.jmedchem.7b01712

Experimental method

X-RAY DIFFRACTION (1.59 Å)