Enhancing Chemotherapy Efficacy: The Role of PROTAC 753B in Targeting BCL-XL/BCL-2 and Eliminating Senescent AML Cells

The study investigates the effectiveness of a novel BCL-XL/BCL-2 PROTAC agent, 753B, in leukemia treatment. The compound was tested on 17 diverse leukemia cell lines, including AML, T-ALL, and MPN-AML types, and was found to induce degradation of BCL-XL and BCL-2 at lower concentrations than the first-generation PROTAC DT2216. 753B demonstrated a dose-dependent decrease in cell viability in AML cell lines and was notably more potent than ABT263 in sensitive cell lines.

The research also revealed that 753B can counteract chemotherapy-induced senescence in AML cells, which is associated with chemoresistance. The PROTAC agent was able to revert the senescence phenotype and induce death in senescent AML cells. The study suggests that the senescent AML population, which expresses higher levels of BCL-XL/2, is particularly susceptible to 753B.

Furthermore, the study observed that the degradation of BCL-XL/2 by 753B was accompanied by an upregulation of MCL-1 in most cell lines tested. This upregulation was linked to an increased dependence on MCL-1, as evidenced by enhanced binding of BIM to MCL-1 and facilitated cytochrome c release. The combination of 753B with an MCL-1 inhibitor showed a synergistic effect in inducing apoptosis.

When tested on blasts from primary AML samples, 753B significantly reduced cell viability with a median IC50 value of 0.36 μM and was more potent than DT2216. It also showed comparable potency to ABT-263 in Venetoclax-resistant AML samples. 753B induced apoptosis in both bulk blasts and CD34+ stem/progenitor cells.

In conclusion, the PROTAC 753B has shown the ability to effectively reduce cell viability and eliminate chemotherapy-induced senescent leukemia cells through the induction of apoptosis. Ongoing in vivo studies are evaluating the combination of 753B with chemotherapy in xenograft models.