MDM2-BCL-X PROTACs enable degradation of BCL-X and stabilization of p53.

Inhibition or degradation of anti-apoptotic protein BCL-X is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-X, the E3 ligases are confined to the commonly used VHL and CRBN. Herein we report the development of MDM2-BCL-X PROTACs using MDM2 as E3 ligase for degradation of BCL-X. Three MDM2-BCL-X PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2/BCL-X inhibitor ABT-263 with different linker length were designed, synthesized, and evaluated in vitro. We found exhibited potent, selective degradation activity against BCL-X and stabilized tumor suppressor p53 in U87, A549 and MV-4-11 cancer cell lines. Moreover, combination of BMM4 and BCL-2 inhibitor ABT-199 showed synergistic antiproliferative activity. The unique dual-functional PROTACs offers an alternative strategy for targeted protein degradation.