Therapeutic potential of BTK targeted degrader in B-cell malignancies harboring ibrutinib-resistant mutation

The long-term efficacy of Ibrutinib is limited by the emergence of resistance mutations (e.g., C481S, L528W). These mutations preclude formation of a covalent bond with BTK, leading to diminished drug efficacy and disease progression. Therefore, novel therapeutic strategy is urgently needed for patients who have acquired resistant mutations of Ibrutinib. Targeted protein degradation represents a potential and powerful means to overcome Ibrutinib resistance. To evaluate BTK degradation as a strategy to overcome ibrutinib resistance, we characterized Bexobrutideg (NX-5948), a novel cereblon E3 ligase-engaging small molecule that induces BTK protein degradation. In vitro , NX-5948 exhibited potent antiproliferative effects against ibrutinib-sensitive and -resistant B-cell malignancy models (including BTK-C481S and BTK-L528W mutants). In vivo , NX-5948 achieved significant tumor growth inhibition in xenografts harboring these resistance mutations, demonstrating its potential to overcome clinical resistance to Ibrutinib. In summary, we have validated the anti-tumor activity of NX-5948 in Ibrutinib-resistant cell lines, both in vitro and in vivo. These findings support targeting BTK degrader could be as a promising strategy to bypass resistance by eliminating mutant BTK in patients with B-cell malignancies.