Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines

Targeting BCL-X_L via PROTACs is a promising strategy in reducing BCL-X_L inhibition associated platelet toxicity. Recently, we reported potent BCL-X_L PROTAC degraders that recruit VHL or CRBN E3 ligase. However, low protein expression or mutation of the responsible E3 ligase has been known to result in decreased protein degradation efficiency of the corresponding PROTACs. To overcome these mechanisms of resistance, PROTACs based on recruiting alternative E3 Ligases could be generated. Thus, we designed and synthesized a series of PROTACs that recruit IAP E3 Ligases for BCL-X_L degradation. Among those PROTACs, compound 8a efficiently degrades BCL-X_L in malignant T-cell lymphoma cell line MyLa 1929 while CRBN-based PROTACs that have high potency in other Cancer cell lines show compromised potency, likely due to the low CRBN expression. Moreover, compared with the parent compound ABT-263, PROTAC 8a shows comparable cell killing effects in MyLa 1929 cells whereas the on-target platelet toxicity is significantly reduced. Our findings expand the anti-tumor spectra of BCL-X_L degraders and further highlight the importance of selecting suitable E3 members to achieve effective cellular activity.