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.

Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton’s Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies

“…NX-2127 maintains degradation activity against the inhibitor-resistant mutant despite reduced binding affinity ( K d = 18 ± 3 nM vs 45 ± 11 nM, by SPR) . These data are consistent with previous work in the degrader field showing relatively little correlation between binding affinity and protein degradation. , The activity of NX-2127 against a range of clinically relevant mutations is described in detail in an accompanying report …”

A Review of Resistance Mechanisms to Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia

“…PROTACs constitute specialized molecules consisting of two linked domains, one that binds to the targeted protein and the other to E3 ubiquitin ligase. Such binding results in the degradation of the targeted protein by the proteasome [74][75][76]. Several BTK degraders, including NX-2127, NX-5948, BGB-16673, ABBV-101, and AC676, were recently under investigation in CLL patients [77][78][79][80][81].…”

Orally Bioavailable Proteolysis-Targeting Chimeras: An Innovative Approach in the Golden Era of Discovering Small-Molecule Cancer Drugs

“…NX-2127 degrades wild-type BTK and ibrutinib-resistant C481S mutant BTK (BTKC481S) in TMD8 cells with a DC 50 of 4.5 and 31 nM, respectively. NX-2127 also degrades both IKZF1 and IKZF3 with a potency of 57 and 36 nM, respectively, which is similar to the approved drug pomalidomide [ 93 ]. The development process of NX-2127 is depicted in Figure 17 , showcasing how the molecule evolved through the systematic refinement of its inhibitors, linkers, and cereblon ligands.…”