4YHF

Bruton's tyrosine kinase in complex with a t-butyl cyanoacrylamide inhibitor

4YHF の概要

• エントリーDOI: 10.2210/pdb4yhf/pdb
• 分子名称: Tyrosine-protein kinase BTK, (2S)-2-({(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}carbonyl)-4,4-dimethylpentanenitrile, SODIUM ION, ... (7 entities in total)
• 機能のキーワード: covalent inhibitor, cyanoacrylamide, cysteine, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67169.96

構造登録者

Paavilainen, V.O.,McFarland, J.M.,Taunton, J. (登録日: 2015-02-27, 公開日: 2015-05-13, 最終更新日: 2024-11-20)

主引用文献

Bradshaw, J.M.,McFarland, J.M.,Paavilainen, V.O.,Bisconte, A.,Tam, D.,Phan, V.T.,Romanov, S.,Finkle, D.,Shu, J.,Patel, V.,Ton, T.,Li, X.,Loughhead, D.G.,Nunn, P.A.,Karr, D.E.,Gerritsen, M.E.,Funk, J.O.,Owens, T.D.,Verner, E.,Brameld, K.A.,Hill, R.J.,Goldstein, D.M.,Taunton, J.
Prolonged and tunable residence time using reversible covalent kinase inhibitors.
Nat.Chem.Biol., 11:525-531, 2015

PubMed Abstract: Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo.

PubMed: 26006010
DOI: 10.1038/nchembio.1817

実験手法

X-RAY DIFFRACTION (2.2 Å)