8GC8

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

Summary for 8GC8

• Entry DOI: 10.2210/pdb8gc8/pdb
• Descriptor: Tyrosine-protein kinase BTK, 5-(piperidin-1-yl)-3-[4-(piperidin-4-yl)anilino]pyrazine-2-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: degrader, complex, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32275.09

Authors

Gajewski, S. (deposition date: 2023-03-01, release date: 2024-01-31, Last modification date: 2024-02-21)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.75 Å)