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

Preprint | 
10.55415/deep-2022-0045.v1
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Mengyang Chang
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.
Feng Gao
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Az, USA.
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Az, USA.
Jing Chen
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Az, USA.
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Az, USA.
Giri Gnawali
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Az, USA.
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Az, USA.
Wei Wang*
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.++Department of Pharmacology and Toxicology, University of Arizona, Tucson, Az, USA.
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ, USA.++Department of Pharmacology and Toxicology, University of Arizona, Tucson, Az, USA.

# contributed equally to this work, * Corresponding author

Abstract

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-BCLXL PROTACs derived from MDM2 inhibitor Nutlin-3, which can also upregulate p53, and BCL-2/BCL-XL inhibitor ABT-263 with different linker length were designed, synthesized, and evaluated in vitro. We found BMM4 exhibited potent, selective degradation activity against BCLXL 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.

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Keywords
BCL-XL ;  MDM2 E3 ligase ;  PROTAC ;  targeted protein degradation
Subject Area
Cancer Biology
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  • 31 Aug 2022 10:20 Version 1
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