Announcing a new publication for Acta Materia Medica journal. Inhibition or degradation of the anti-apoptotic protein BCL-XL is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-XL, the choice of E3 ligase has been restricted to VHL and CRBN.
The authors of this article report the development of MDM2-BCL-XL PROTACs using MDM2 as an E3 ligase for degradation of BCL-XL. Three MDM2-BCL-XL PROTACs derived from the MDM2 inhibitor Nutlin-3, which also upregulates p53, and the BCL-2/BCL-XL inhibitor ABT-263 with different linker lengths were designed, synthesized and evaluated in vitro. BMM4 exhibited potent, selective degradation activity against BCL-XL, and stabilized the tumor suppressor p53 in U87, A549 and MV-4-11 cancer cell lines. Moreover, the combination of BMM4 and the BCL-2 inhibitor ABT-199 showed synergistic antiproliferative activity.
These unique bifunctional PROTACs offer an alternative strategy for targeted protein degradation.
Article Reference: Mengyang Chang, Feng Gao and Jing Chen et al. MDM2-BCL-XL PROTACs enable degradation of BCL-XL and stabilization of p53. Acta Materia Medica. Vol. 1(3):333-342. DOI: 10.15212/AMM-2022-0022
Keywords: BCL-XL , MDM2 E3 ligase, PROTAC, targeted protein degradation
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