ARV-825-induced BRD4 Protein Degradation As a Therapy for Thyroid Carcinoma

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2020 Mar 13

PMID 32163373

Citations 13

Authors

Ling He

Chen Chen

Guoyu Gao

Kun Xu

Zhaoqun Ma

Affiliations

Soon will be listed here.

Abstract

Bromodomain-containing protein 4 (BRD4) is overexpressed in thyroid carcinoma, represents as an important therapeutic target. ARV-825 is a novel cereblon-based PROTAC (Proteolysis Targeting Chsimera) compound. It can induce fast and sustained BRD4 protein degradation. Its potential effect in human thyroid carcinoma cells was studied here. In TPC-1 cells and primary human thyroid carcinoma cells, ARV-825 potently inhibited cell viability, proliferation and migration. Furthermore, ARV-825 induced robust apoptosis activation in the thyroid carcinoma cells. ARV-825 induced BRD4 protein degradation and downregulation of its targets, including c-Myc, Bcl-xL and cyclin D1 in thyroid carcinoma cells. It was significantly more potent in inhibiting thyroid carcinoma cells than the known small molecule BRD4 inhibitors. studies demonstrated that ARV-825 oral administration potently suppressed TPC-1 xenograft tumor growth in severe combined immunodeficient mice. BRD4 protein degradation as well as c-Myc, Bcl-xL and cyclin D1 downregulation were detected in ARV-825-treated TPC-1 tumor tissues. Taken together, ARV-825 induces BRD4 protein degradation and inhibits thyroid carcinoma cell growth and .

Citing Articles

The Common Hallmarks and Interconnected Pathways of Aging, Circadian Rhythms, and Cancer: Implications for Therapeutic Strategies.

Wang J, Shao F, Yu Q, Ye L, Wusiman D, Wu R Research (Wash D C). 2025; 8:0612.

PMID: 40046513 PMC: 11880593. DOI: 10.34133/research.0612.

Unlocking the Potential of Camel Milk-Derived Exosomes as Novel Delivery Systems: Enhanced Bioavailability of ARV-825 PROTAC for Cancer Therapy.

Nathani A, Aare M, Sun L, Bagde A, Li Y, Rishi A Pharmaceutics. 2024; 16(8.

PMID: 39204415 PMC: 11359469. DOI: 10.3390/pharmaceutics16081070.

PROTAC Beyond Cancer- Exploring the New Therapeutic Potential of Proteolysis Targeting Chimeras.

Bhole R, Patil S, Kapare H, Chikhale R, Gurav S Curr Top Med Chem. 2024; 24(23):2050-2073.

PMID: 38963108 DOI: 10.2174/0115680266309968240621072550.

Cellular senescence in cancer: molecular mechanisms and therapeutic targets.

Jin P, Duan X, Li L, Zhou P, Zou C, Xie K MedComm (2020). 2024; 5(5):e542.

PMID: 38660685 PMC: 11042538. DOI: 10.1002/mco2.542.

ARV-825 Showed Antitumor Activity against BRD4-NUT Fusion Protein by Targeting the BRD4.

Yang L, Jing Y, Xia X, Yin X J Oncol. 2023; 2023:9904143.

PMID: 38130463 PMC: 10735731. DOI: 10.1155/2023/9904143.

References

Korb E, Herre M, Zucker-Scharff I, Darnell R, Allis C . BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice. Nat Neurosci. 2015; 18(10):1464-73. PMC: 4752120. DOI: 10.1038/nn.4095. View

Li G, Zhou L, Yang H, He X, Duan Y, Wu F . Ninjurin 2 overexpression promotes human colorectal cancer cell growth and . Aging (Albany NY). 2019; 11(19):8526-8541. PMC: 6814613. DOI: 10.18632/aging.102336. View

Sun B, Fiskus W, Qian Y, Rajapakshe K, Raina K, Coleman K . BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mantle cell lymphoma cells. Leukemia. 2017; 32(2):343-352. DOI: 10.1038/leu.2017.207. View

Iftner T, Haedicke-Jarboui J, Wu S, Chiang C . Involvement of Brd4 in different steps of the papillomavirus life cycle. Virus Res. 2016; 231:76-82. PMC: 5325811. DOI: 10.1016/j.virusres.2016.12.006. View

Zuber J, Shi J, Wang E, Rappaport A, Herrmann H, Sison E . RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011; 478(7370):524-8. PMC: 3328300. DOI: 10.1038/nature10334. View

Coude M, Braun T, Berrou J, Dupont M, Bertrand S, Masse A . BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015; 6(19):17698-712. PMC: 4627339. DOI: 10.18632/oncotarget.4131. View

Saenz D, Fiskus W, Qian Y, Manshouri T, Rajapakshe K, Raina K . Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia. 2017; 31(9):1951-1961. PMC: 5537055. DOI: 10.1038/leu.2016.393. View

Vuong H, Altibi A, Abdelhamid A, Ngoc P, Quan V, Tantawi M . The changing characteristics and molecular profiles of papillary thyroid carcinoma over time: a systematic review. Oncotarget. 2016; 8(6):10637-10649. PMC: 5354688. DOI: 10.18632/oncotarget.12885. View

Shi J, Vakoc C . The mechanisms behind the therapeutic activity of BET bromodomain inhibition. Mol Cell. 2014; 54(5):728-36. PMC: 4236231. DOI: 10.1016/j.molcel.2014.05.016. View

10.

Lu J, Qian Y, Altieri M, Dong H, Wang J, Raina K . Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chem Biol. 2015; 22(6):755-63. PMC: 4475452. DOI: 10.1016/j.chembiol.2015.05.009. View

11.

Xiang T, Bai J, She C, Yu D, Zhou X, Zhao T . Bromodomain protein BRD4 promotes cell proliferation in skin squamous cell carcinoma. Cell Signal. 2017; 42:106-113. DOI: 10.1016/j.cellsig.2017.10.010. View

12.

Shen G, Jiang M, Pu J . Dual inhibition of BRD4 and PI3K by SF2523 suppresses human prostate cancer cell growth in vitro and in vivo. Biochem Biophys Res Commun. 2017; 495(1):567-573. DOI: 10.1016/j.bbrc.2017.11.062. View

13.

Zhou L, Li P, Cai S, Li G, Liu F . Ninjurin2 overexpression promotes glioma cell growth. Aging (Albany NY). 2019; 11(23):11136-11147. PMC: 6932907. DOI: 10.18632/aging.102515. View

14.

La Vecchia C, Malvezzi M, Bosetti C, Garavello W, Bertuccio P, Levi F . Thyroid cancer mortality and incidence: a global overview. Int J Cancer. 2014; 136(9):2187-95. DOI: 10.1002/ijc.29251. View

15.

Xu K, Chen D, Qian D, Zhang S, Zhang Y, Guo S . AZD5153, a novel BRD4 inhibitor, suppresses human thyroid carcinoma cell growth in vitro and in vivo. Biochem Biophys Res Commun. 2018; 499(3):531-537. DOI: 10.1016/j.bbrc.2018.03.184. View

16.

Lu Q, Ding X, Huang T, Zhang S, Li Y, Xu L . BRD4 degrader ARV-825 produces long-lasting loss of BRD4 protein and exhibits potent efficacy against cholangiocarcinoma cells. Am J Transl Res. 2019; 11(9):5728-5739. PMC: 6789278. View

17.

Wang Y, Wang W, Sun H . Bromodomain‑containing protein 4 is critical for the antiproliferative and pro‑apoptotic effects of gambogic acid in anaplastic thyroid cancer. Int J Mol Med. 2018; 42(1):161-170. PMC: 5979940. DOI: 10.3892/ijmm.2018.3642. View

18.

Chen R, Yik J, Lew Q, Chao S . Brd4 and HEXIM1: multiple roles in P-TEFb regulation and cancer. Biomed Res Int. 2014; 2014:232870. PMC: 3925632. DOI: 10.1155/2014/232870. View

19.

Abruzzese M, Bilotta M, Fionda C, Zingoni A, Soriani A, Vulpis E . Inhibition of bromodomain and extra-terminal (BET) proteins increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of cMYC-IRF4-miR-125b interplay. J Hematol Oncol. 2016; 9(1):134. PMC: 5131470. DOI: 10.1186/s13045-016-0362-2. View

20.

Davies L, Welch H . Current thyroid cancer trends in the United States. JAMA Otolaryngol Head Neck Surg. 2014; 140(4):317-22. DOI: 10.1001/jamaoto.2014.1. View