Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127 Journal Article
| Authors: | Montoya, S.; Bourcier, J.; Noviski, M.; Lu, H.; Thompson, M. C.; Chirino, A.; Jahn, J.; Sondhi, A. K.; Gajewski, S.; Tan, Y. S.; 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.; Rios, M. S. G. D. L.; Ye, J.; Risso, C. B.; 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.; Skånland, S. S.; Brown, R. J.; Mato, A. R.; Hansen, G. M.; Abdel-Wahab, O.; Taylor, J. |
| Article Title: | Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127 |
| 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. © 2024 American Association for the Advancement of Science. All rights reserved. |
| Keywords: | signal transduction; genetics; mutation; metabolism; protein kinase inhibitor; protein; transcription factor; drug resistance; enzyme activity; inhibitor; phosphorylation; transcription factors; protein kinase inhibitors; chronic lymphatic leukemia; leukemia, lymphocytic, chronic, b-cell; disease treatment; ikaros transcription factor; degradation; cell; bruton tyrosine kinase; humans; human; agammaglobulinaemia tyrosine kinase; ikzf1 protein, human |
| Journal Title: | Science |
| Volume: | 383 |
| Issue: | 6682 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2024-02-02 |
| Start Page: | eadi5798 |
| Language: | English |
| DOI: | 10.1126/science.adi5798 |
| PUBMED: | 38301010 |
| PROVIDER: | scopus |
| PMCID: | PMC11103405 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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