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

ABSTRACT: Inhibition or degradation of anti-apoptotic protein BCL-X_L is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-X_L, the E3 ligases are confined to the commonly used VHL and CRBN. Herein we report the development of MDM2-BCL-X_L PROTACs using MDM2 as E3 ligase for degradation of BCL-X_L. Three MDM2-BCL-X_L PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2/BCL-X_L inhibitor ABT-263 with different linker length were designed, synthesized, and evaluated in vitro. We found BMM4 exhibited potent, selective degradation activity against BCL-X_L 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.

SUBMITTER: Chang M

PROVIDER: S-EPMC10004178 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Chang Mengyang M Gao Feng F Chen Jing J Gnawali Giri G Wang Wei W

Acta materia medica 20220701 3

Inhibition or degradation of anti-apoptotic protein BCL-XL is a viable strategy for cancer treatment. Despite the recent development of PROTACs for degradation of BCL-XL, the E3 ligases are confined to the commonly used VHL and CRBN. Herein we report the development of MDM2-BCL-XL PROTACs using MDM2 as E3 ligase for degradation of BCL-XL. Three MDM2-BCL-XL PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2 ...[more]

PMID: 36910255

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