8TU5

Bruton's tyrosine kinase in complex with covalent inhibitor compound 27

8TU5 の概要

• エントリーDOI: 10.2210/pdb8tu5/pdb
• 関連するPDBエントリー: 8TU3 8TU4
• 分子名称: Tyrosine-protein kinase BTK, 1-[(1S,5S,6S)-6-methyl-6-{[(6M,8R)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy}-2-azabicyclo[3.2.0]heptan-2-yl]propan-1-one (3 entities in total)
• 機能のキーワード: kinase, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33060.92

構造登録者

Metrick, C.M. (登録日: 2023-08-15, 公開日: 2024-06-26, 最終更新日: 2024-10-16)

主引用文献

Himmelbauer, M.K.,Bajrami, B.,Basile, R.,Capacci, A.,Chen, T.,Choi, C.K.,Gilfillan, R.,Gonzalez-Lopez de Turiso, F.,Gu, C.,Hoemberger, M.,Johnson, D.S.,Jones, J.H.,Kadakia, E.,Kirkland, M.,Lin, E.Y.,Liu, Y.,Ma, B.,Magee, T.,Mantena, S.,Marx, I.E.,Metrick, C.M.,Mingueneau, M.,Murugan, P.,Muste, C.A.,Nadella, P.,Nevalainen, M.,Parker Harp, C.R.,Pattaropong, V.,Pietrasiewicz, A.,Prince, R.J.,Purgett, T.J.,Santoro, J.C.,Schulz, J.,Sciabola, S.,Tang, H.,Vandeveer, H.G.,Wang, T.,Yousaf, Z.,Helal, C.J.,Hopkins, B.T.
Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.
J.Med.Chem., 67:8122-8140, 2024

PubMed Abstract: Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 () demonstrated efficacy in disease-relevant preclinical models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.

PubMed: 38712838
DOI: 10.1021/acs.jmedchem.4c00220

実験手法

X-RAY DIFFRACTION (2.1 Å)