Related Experiment Video
Updated: Feb 27, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and nuclear factor-κB (NF-κB) target genes that undermines the growth and survival of mantle cell lymphoma (MCL) cells. However, BET bromodomain inhibitor (BETi) treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4 that potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1 and the NF-κB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the levels of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared with ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Cotreatment of ARV-771 with ibrutinib or the BCL2 antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior preclinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or -resistant MCL.
Insights
BET-PROTACs degrade bromodomain extraterminal proteins (BETPs) more effectively than BET inhibitors, leading to greater apoptosis in mantle cell lymphoma (MCL) cells, including those resistant to ibrutinib.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bromodomain extraterminal protein (BETP) inhibitors (BETi) target oncoproteins and nuclear factor-κB (NF-κB) pathways, crucial for mantle cell lymphoma (MCL) cell growth.
- BETi efficacy is limited by BETP accumulation and incomplete BRD4 inhibition.
- BET-PROTACs offer an alternative by degrading BETPs via E3-ubiquitin ligase recruitment.
Purpose of the Study:
- To compare the efficacy of BET-PROTACs (ARV-825, ARV-771) with BET inhibitors (BETi) in mantle cell lymphoma (MCL) models.
- To evaluate the in vivo therapeutic potential of BET-PROTACs in MCL.
- To assess synergistic effects of BET-PROTACs in combination with other MCL therapies.
Main Methods:
- Utilized BET-PROTACs (ARV-825, ARV-771) and BET inhibitors (OTX015) in MCL cell lines and in vivo mouse models.
- Assessed apoptosis, mRNA, and protein expression changes following treatment.
- Investigated combination therapies with ibrutinib, venetoclax, and palbociclib.
Main Results:
- BET-PROTACs induced greater apoptosis in MCL cells, including ibrutinib-resistant cases, compared to BETi.
- BET-PROTACs led to significant depletion of oncogenic proteins (c-Myc, CDK4, cyclin D1) and NF-κB targets (Bcl-xL, XIAP, BTK).
- ARV-771 demonstrated superior in vivo efficacy, inhibiting tumor growth and improving survival in mice compared to OTX015.
- Combination therapy with ARV-771 synergistically enhanced apoptosis in MCL cells.
Conclusions:
- BET-PROTACs exhibit superior preclinical activity against mantle cell lymphoma compared to BET inhibitors.
- BET-PROTACs represent a promising therapeutic strategy for both ibrutinib-sensitive and -resistant MCL.
- Further in vivo evaluation of BET-PROTACs is warranted for MCL treatment.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:31The Intrinsic Apoptotic Pathway