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

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…

• MS
  Memorial Sloan-Kettering Cancer Center

  Award: P30 CA08748
• EP
  Edward P. Evans Foundation

  Award: R01 HL128239
• PF
  Philippe Foundation
• CF
  Cycle for Survival

  Award: P50 CA254838
• SC
  Sylvester Comprehensive Cancer Center, University of Miami Health Systems
• FD
  Fondation de France
• NF
  Norges Forskningsråd

  Awards: 294916, 322898
• NI
  National Institutes of Health

  Awards: R01 CA242020, R01 CA251138, K08CA230319, CA240139, P30 CA08748, R01 HL128239, CA08748, P50 CA254838-01, P30 CA240139
• MA
  Marie-Josée and Henry R. Kravis Center for Molecular Oncology
• NH
  National Heart, Lung, and Blood Institute

  Awards: R01 HL128239, HL128239
• NC
  National Cancer Institute

  Awards: R01 CA251138, R01 CA242020, CA254838-01, CA240139, R01 HL128239, P50 CA254838, CA242020, P30 CA240139, K08CA230319, P30 CA08748, CA08748, P50 CA254838-01
• NC
  National Center for Advancing Translational Sciences

  Award: P30 CA08748