9YT9

A428D mutant of Bruton's tyrosine kinase

Summary for 9YT9

• Entry DOI: 10.2210/pdb9yt9/pdb
• Descriptor: Tyrosine-protein kinase BTK, 1,2-ETHANEDIOL (3 entities in total)
• Functional Keywords: kinase dead mutant, clinical mutation, autoinhibited kinase, signaling protein, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 31679.36

Authors

Gajewski, S. (deposition date: 2025-10-20, release date: 2026-07-15, Last modification date: 2026-08-05)

Primary citation

Sievers, Q.,Lu, H.,Cool, A.,Gajewski, S.,Kong, T.,Noviski, M.A.,Whelan, S.,Wang, Y.,Mendoza Navarrete, L.,Mi, X.,Ficici, E.,Mukerji, R.,Iuliano, J.N.,Ye, J.,Sanchez Garcia De Los Rios, M.,Bousquet, H.,Tan, M.,Brathaban, N.,Narasappa, N.,Lu, Y.W.,Elechko, J.,Maron, M.I.,Phelps, C.B.,Rahman, J.,Notti, R.Q.,Sekeres, S.,Lamkin, E.N.,Bravo, E.,Alencar, A.,Ewalt, M.D.,Islam, P.,Mato, A.R.,Roeker, L.,Bhatt, S.,Taylor, J.,Thompson, M.C.,Hansen, G.M.,Abdel-Wahab, O.
Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors.
Cancer Discov, 2026

PubMed Abstract: Early-phase clinical trials of Bruton's tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate clashes with the adenine ring of ATP and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies.

PubMed: 42484277
DOI: 10.1158/2159-8290.CD-26-0251

Experimental method

X-RAY DIFFRACTION (1.8 Å)