Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.

Publication Type	Academic Article
Authors	Montoya S, Bourcier J, Noviski M, Lu H, Thompson M, Chirino A, Jahn J, Sondhi A, Gajewski S, Tan Y, Yung S, Urban A, Wang E, Han C, Mi X, Kim W, Sievers Q, Auger P, Bousquet H, Brathaban N, Bravo B, Gessner M, Guiducci C, Iuliano J, Kane T, Mukerji R, Reddy P, Powers J, Sanchez Garcia de Los Rios M, Ye J, Barrientos Risso C, Tsai D, Pardo G, Notti R, Pardo A, Affer M, Nawaratne V, Totiger T, Pena-Velasquez C, Rhodes J, Zelenetz A, Alencar A, Roeker L, Mehta S, Garippa R, Linley A, Soni R, Skånland S, Brown R, Mato A, Hansen G, Abdel-Wahab O, Taylor J
Journal	Science
Volume	383
Issue	6682
Pagination	eadi5798
Date Published	02/02/2024
ISSN	1095-9203
Keywords	Agammaglobulinaemia Tyrosine Kinase, Ikaros Transcription Factor, Leukemia, Lymphocytic, Chronic, B-Cell, Protein Kinase Inhibitors, Proteolysis, Drug Resistance, Neoplasm
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.
DOI	10.1126/science.adi5798
PubMed ID	38301010
PubMed Central ID	PMC11103405