8GC8

Bruton's tyrosine kinase L528W mutant in complex with 5-(piperidin-1-yl)-3-{[4-(piperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide

8GC8 の概要

• エントリーDOI: 10.2210/pdb8gc8/pdb
• 分子名称: Tyrosine-protein kinase BTK, 5-(piperidin-1-yl)-3-[4-(piperidin-4-yl)anilino]pyrazine-2-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: degrader, complex, signaling protein
• 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: 32275.09

構造登録者

Gajewski, S. (登録日: 2023-03-01, 公開日: 2024-01-31, 最終更新日: 2024-02-21)

主引用文献

Montoya, S.,Bourcier, J.,Noviski, M.,Lu, H.,Thompson, M.C.,Chirino, A.,Jahn, J.,Sondhi, A.K.,Gajewski, S.,Tan, Y.S.M.,Yung, S.,Urban, A.,Wang, E.,Han, C.,Mi, X.,Kim, W.J.,Sievers, Q.,Auger, P.,Bousquet, H.,Brathaban, N.,Bravo, B.,Gessner, M.,Guiducci, C.,Iuliano, J.N.,Kane, T.,Mukerji, R.,Reddy, P.J.,Powers, J.,Sanchez Garcia de Los Rios, M.,Ye, J.,Barrientos Risso, C.,Tsai, D.,Pardo, G.,Notti, R.Q.,Pardo, A.,Affer, M.,Nawaratne, V.,Totiger, T.M.,Pena-Velasquez, C.,Rhodes, J.M.,Zelenetz, A.D.,Alencar, A.,Roeker, L.E.,Mehta, S.,Garippa, R.,Linley, A.,Soni, R.K.,Skanland, S.S.,Brown, R.J.,Mato, A.R.,Hansen, G.M.,Abdel-Wahab, O.,Taylor, J.
Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.
Science, 383:eadi5798-eadi5798, 2024

PubMed Abstract: Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

PubMed: 38301010
DOI: 10.1126/science.adi5798

実験手法

X-RAY DIFFRACTION (1.75 Å)