5VFI

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

5VFI の概要

• エントリーDOI: 10.2210/pdb5vfi/pdb
• 分子名称: 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)
• 機能のキーワード: protein kinase inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q06187
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32951.75

構造登録者

Steinbacher, S.,Eigenbrot, C. (登録日: 2017-04-07, 公開日: 2018-02-28, 最終更新日: 2024-03-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.59 Å)