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

Mengyang Chang; Feng Gao; Jing Chen; Giri Gnawali; Wei Wang

doi:10.15212/AMM-2022-0022

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

Mengyang Chang
, Feng Gao
, Jing Chen
, Giri Gnawali
, Wei Wang

Pharmacology and Toxicology

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Inhibition or degradation of the 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 choice of E3 ligase has been restricted to VHL and CRBN. Herein, we report the development of MDM2-BCL-X_L PROTACs using MDM2 as an E3 ligase for degradation of BCL-X_L. Three MDM2-BCL-X_L PROTACs derived from the MDM2 inhibitor Nutlin-3, which also upregulates p53, and the BCL-2/BCL-X_L inhibitor ABT-263 with different linker lengths were designed, synthesized and evaluated in vitro. BMM4 exhibited potent, selective degradation activity against BCL-X_L, 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.

Original language	English (US)
Pages (from-to)	333-342
Number of pages	10
Journal	Acta Materia Medica
Volume	1
Issue number	3
DOIs	https://doi.org/10.15212/AMM-2022-0022
State	Published - 2022

Keywords

BCL-X
MDM2 E3 ligase
PROTAC
targeted protein degradation

ASJC Scopus subject areas

Pathophysiology
Complementary and Manual Therapy
Occupational Therapy
Inorganic Chemistry
Molecular Medicine
General Pharmacology, Toxicology and Pharmaceutics

Access to Document

10.15212/AMM-2022-0022

Cite this

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title = "MDM2-BCL-XL PROTACs enable degradation of BCL-XL and stabilization of p53",

abstract = "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. Herein, we 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.",

keywords = "BCL-X, MDM2 E3 ligase, PROTAC, targeted protein degradation",

author = "Mengyang Chang and Feng Gao and Jing Chen and Giri Gnawali and Wei Wang",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors.",

year = "2022",

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T1 - MDM2-BCL-XL PROTACs enable degradation of BCL-XL and stabilization of p53

AU - Chang, Mengyang

AU - Gao, Feng

AU - Chen, Jing

AU - Gnawali, Giri

AU - Wang, Wei

PY - 2022

Y1 - 2022

N2 - 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. Herein, we 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.

AB - 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. Herein, we 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.

KW - BCL-X

KW - MDM2 E3 ligase

KW - PROTAC

KW - targeted protein degradation

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