BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes
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Abstract
Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, with relapse due to drug resistance. Recent studies show that bromodomains and extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising a BET inhibitor conjugated with cereblon ligand, was recently developed to attenuate the growth of multiple tumors in vitro and in vivo. However, the functional and molecular mechanisms of ARV-825 in T-ALL remain unclear. This study aimed to investigate the therapeutic efficacy and potential mechanism of ARV-825 in T-ALL. Methods: Expression of the BRD4 were determined in pediatric T-ALL samples and differential gene expression after ARV-825 treatment was explored by RNA-seq and quantitative reverse transcription-polymerase chain reaction. T-ALL cell viability was measured by CCK8 assay after ARV-825 administration. Cell cycle was analyzed by propidium iodide (PI) staining and apoptosis was assessed by Annexin V/PI staining. BRD4, BRD3 and BRD2 proteins were detected by western blot in cells treated with ARV-825. The effect of ARV-825 on T-ALL cells was analyzed in vivo. The functional and molecular pathways involved in ARV-825 treatment of T-ALL were verified by western blot and chromatin immunoprecipitation (ChIP). Results: BRD4 expression was higher in pediatric T-ALL samples compared with T-cells from healthy donors. High BRD4 expression indicated a poor outcome. ARV-825 suppressed cell proliferation in vitro by arresting the cell cycle and inducing apoptosis, with elevated poly-ADP ribose polymerase and cleaved caspase 3. BRD4, BRD3, and BRD2 were degraded in line with reduced cereblon expression in T-ALL cells. ARV-825 had a lower IC50 in T-ALL cells compared with JQ1, dBET1 and OTX015. ARV-825 perturbed the H3K27Ac-Myc pathway and reduced c-Myc protein levels in T-ALL cells according to RNA-seq and ChIP. In the T-ALL xenograft model, ARV-825 significantly reduced tumor growth and led to the dysregulation of Ki67 and cleaved caspase 3. Moreover, ARV-825 inhibited cell proliferation by depleting BET and c-Myc proteins in vitro and in vivo. Conclusions: BRD4 indicates a poor prognosis in T-ALL. The BRD4 degrader ARV-825 can effectively suppress the proliferation and promote apoptosis of T-ALL cells via BET protein depletion and c-Myc inhibition, thus providing a new strategy for the treatment of T-ALL.
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ARV-825 (218) effectively degrades BRD4 protein while inhibiting proliferation and inducing apoptosis in cellular in vitro experiments, and in primary drug-resistant T-ALL cells it eradicates cells through BRD4 degradation, reducing c-Myc expression.
“In 2021, Hu’s team revealed, through cellular in vitro experiments, that ARV-825 (218) effectively degraded the BRD4 protein while inhibiting proliferation and inducing apoptosis (Table 4). In primary drug-resistant T-cell acute lymphoblastic leukemia (T-ALL) cells, the researchers observed that ARV-825 eradicated cells through BRD4 protein degradation, significantly reducing c-Myc expression.518”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [518]
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- Authors
- Wu, S., Jiang, Y., Hong, Y., Chu, X., Zhang, Z., Tao, Y., Fan, Z., Bai, Z., Li, X., Chen, Y., Li, Z., Ding, X., Lv, H., Du, X., Lim, S. L., Zhang, Y., Huang, S., Lu, J., Pan, J., & Hu, S.
- Affiliations
- Soochow University (CN)
- Nanjing University of Chinese Medicine (CN)
- Cincinnati Children's Hospital Medical Center (US)
- Saint Michael's Medical Center (US)
- Corresponding author
- Pan, Jian
- Hu, Shaoyan
- ORCID
- Venue
- Cancer Cell International
- Published
- 2021-04-22
- Volume
- 21
- Issue
- 1
- Pages
- 230-230
- ISSN
- 1475-2867 (ISSN-L)
- PMC
- PMC8061034
- OpenAlex
- W3113804806
- Cited by
- 81
- References
- 37
- Citations by year
- 2026: 18 · 2025: 13 · 2024: 11 · 2023: 23 · 2022: 12 · 2021: 4
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cancer Cell International (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82072767)
- Innovative Research Group Project of the National Natural Science Foundation of China (81770145)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- ARV-825, BRD4, T-cell acute lymphoblastic leukemia, PROTAC degraders, cereblon ligands, BET inhibitors, MYC pathway, H3K27 acetylation, c-Myc, BRD3, BRD2, apoptosis, cell cycle arrest, pediatric leukemia, xenograft tumor growth
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