Bgb-11417: A novel BCL2 inhibitor with robust antileukemic activity in T-cell acute lymphoblastic leukemia, alone or with vincristine

Abstract

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a malignant disorder characterized by the abnormal proliferation of immature T lymphocytes. Adult T-ALL patients experience refractory relapses due to complex genetic mutations, resulting in a 5-year survival rate of less than 50% (Raetz and Teachey 2016). The maturation stage of T-ALL cells determines the dependency on Bcl-2 and Bcl-xL, as well as sensitivity to BCL2 inhibitor (van Delft and Huang 2006). BGB-14417, a novel Bcl-2 inhibitor, demonstrates greater selectivity and efficacy compared to venetoclax (ABT-199), inhibiting Bcl-2 at lower concentrations while increasing selectivity for Bcl-xL. These properties suggest that BGB-14417 may be effective in both Bcl-2-high ETP-ALL and other T-ALL subtypes. To assess the anti-leukemic activity of BGB-11417, we conducted drug sensitivity assays using conventional T-ALL cell lines (Jurkat and MOLT4), the early T-cell precursor ALL (ETP-ALL) cell line ZYXY-T1, and primary blasts derived from patient samples. Cell viability was measured using the Cell Counting Kit-8 (CCK-8) assay. BGB-11417 exhibited greater potency than ABT-199 across all tested cell types. In ZYXY-T1 cells, BGB-11417 demonstrated superior anti-leukemic efficacy compared with ABT-199 both in vitro and in vivo. Western blot analysis showed that BGB-11417 more effectively induced the apoptosis markers cleaved caspase-3 and cleaved PARP. In mouse cell line–derived xenograft (CDX) models, BGB-11417 also showed enhanced in vivo anti-leukemic activity relative to ABT-199. However, its efficacy is limited by BCL2 expression in classic T-ALL. Therefore, multiple chemotherapeutic and targeted agents were evaluated for their potential to synergize with BGB-11417. Among them, vincristine (VCR) exhibited the strongest synergy with BGB-11417 in Jurkat and MOLT4 cells. Synergistic interactions were quantified using SynergyFinder 2.0. Apoptosis and cell cycle alterations were assessed in parallel, and JC-1 staining revealed changes in mitochondrial membrane potential. As expected, each experimental readout consistently demonstrated a strong synergistic effect between BGB-11417 and VCR, which was superior to that observed with ABT-199. To elucidate the mechanism of synergy, transcriptomic sequencing was performed. Combination with VCR and BGB-11417 resulted in downregulation of MYC, G2M, and E2F pathways—all of which are functionally linked to Notch1 signaling. These findings suggest a possible suppression of the Notch1 pathway. Activating mutations of NOTCH1 is observed in more than 65% of T-ALL patients (Sanchez-Martin and Ferrando 2017). Jurkat and MOLT-4 also carry activating mutations in Notch1. In Jurkat cells, RT-qPCR showed no significant change in Notch1 mRNA levels following combination treatment. However, Western blot analysis revealed a marked decrease in Notch1 protein levels. Cycloheximide (CHX) assay was used to assess protein degradation dynamics. Notch1 protein levels declined more rapidly in the combination group compared to single-agent and control groups following CHX exposure, indicating that the reduction in Notch1 is primarily due to enhanced protein degradation. Our study demonstrates that BGB-11417 exhibits potent anti-leukemic activity in ETP-ALL and exerts a synergistic effect with VCR in classic T-ALL. Both as a single agent and in combination with VCR, BGB-11417 shows superior efficacy compared to ABT-199. These results demonstrate that BGB-11417 as a promising therapeutic agent for T-ALL and should be considered in future clinical trials.