BET inhibitors(Bromodomain and extra terminal domain protein inhibitors), BRD4 inhibitors(Bromodomain-containing protein 4 inhibitors), CRBN inhibitors(Cereblon inhibitors)

+ [1]

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication

Hematologic NeoplasmsSolid tumor

Inactive Indication-

Originator Organization

Arvinas, Inc.

Active Organization

Medchemexpress LLC

University Of Dundee

Inactive Organization

Arvinas, Inc.

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC46H47ClN8O9S

InChIKeyRWLOGRLTDKDANT-TYIYNAFKSA-N

CAS Registry1818885-28-7

100 Clinical Results associated with ARV-825

100 Translational Medicine associated with ARV-825

100 Patents (Medical) associated with ARV-825

Literatures (Medical) associated with ARV-825

01 Jan 2025·International Journal of Pharmaceutics

Liposomes-mediated enhanced antitumor effect of docetaxel with BRD4-PROTAC as synergist for breast cancer chemotherapy/immunotherapy

Article

Author: Chen, Xixi ; Wen, Lijuan ; Cui, Binghui ; Zhu, Zengyan ; Chen, Weiliang ; Qiu, Caisheng ; Yan, Qingyi ; Li, Fang

It has been reported that proteolysis-targeting chimeras (PROTACs) can effectively degrade intracellular oncogenic proteins, providing an ideal strategy for cancer treatment. ARV825, a bromodomain-containing protein 4 (BRD4)-PROTAC, has demonstrated the capacity to enhance the antitumor effect of the classic chemotherapeutic agent docetaxel (DTX). However, there are three major challenges to the broader in vivo application of ARV825: poor solubility, poor permeability, and off-target effects. Additionally, the efficient co-delivery of ARV825 and DTX to tumor tissues for a synergistic therapeutic effect remains unresolved. In this study, liposomes were utilized as co-delivery vehicles for ARV825 and DTX to effectively address these issues. The well-established liposomes significantly improved the solubility of both ARV825 and DTX while maintaining a sustained release profile in blood-mimetic conditions. The co-loaded liposomes accumulated in tumor tissues via the enhanced permeability and retention (EPR) effect. After internalization, ARV825 effectively degraded intracellular BRD4 proteins and downregulated the expression of both Bcl-2 and PD-L1 proteins, thereby increasing tumor cell apoptosis and enhancing the tumor immune response. This, in turn, augmented the antitumor effect of DTX in vivo without undesired side effects. In conclusion, BRD4-PROTAC may serve as a promising synergistic agent alongside the conventional chemotherapeutic agent DTX, with liposomes functioning as effective co-delivery vehicles.

01 Sep 2024·Current Cancer Drug Targets

Bromodomain Protein-directed Agents and MYC in Small Cell Lung Cancer

Review

Author: Rath, Barbara ; Hamilton, Gerhard ; Stickler, Sandra

Abstract::Small cell lung cancer (SCLC) has a dismal prognosis. In addition to the inactivation of the tumor suppressors TP53 and RB1, tumor-promoting MYC and paralogs are frequently overexpressed in this neuroendocrine carcinoma. SCLC exhibits high resistance to second-line chemotherapy and all attempts of novel drugs and targeted therapy have failed so far to achieve superior survival. MYC and paralogs have key roles in the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism. In SCLC, MYC-L and MYC regulate the neuroendocrine dedifferentiation of SCLC cells from Type A (ASCL1 expression) to the other SCLC subtypes. Targeting MYC to suppress tumor growth is difficult due to the lack of suitable binding pockets and the most advanced miniprotein inhibitor Omomyc exhibits limited efficacy. MYC may be targeted indirectly via the bromodomain (BET) protein BRD4, which activates MYC transcription, by specific BET inhibitors that reduce the expression of this oncogenic driver. Here, novel BET-directed Proteolysis Targeting Chimeras (PROTACs) are discussed that show high antiproliferative activity in SCLC. Particularly, ARV-825, targeting specifically BRD4, exhibits superior cytotoxic effects on SCLC cell lines and may become a valuable adjunct to SCLC combination chemotherapy.

01 Sep 2024·Molecular Therapy - Nucleic Acids

Novel gene therapy for drug-resistant melanoma: Synergistic combination of PTEN plasmid and BRD4 PROTAC-loaded lipid nanocarriers

Article

Author: Dukhande, Vikas ; Vemana, Hari Priya ; Patel, Ketan ; Saraswat, Aishwarya

Patients suffering from BRAF mutant melanoma have tumor recurrence within merely 7 months of treatment with a potent BRAF inhibitor (BRAFi) like vemurafenib. It has been proven that diverse molecular pathways driving BRAFi resistance converge to activation of c-Myc in melanoma. Therefore, we identified a novel combinatorial therapeutic strategy by targeting loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and upregulated BRD4 oncoprotein as Myc-dependent vulnerabilities of drug-resistant melanoma. Being promising therapeutic targets, we decided to concomitantly deliver PTEN plasmid and BRD4 targeted PROteolysis-TArgeting Chimera (ARV) to drug the "undruggable" c-Myc in BRAFi-resistant melanoma. Since PTEN plasmid and ARV are distinct in their physicochemical properties, we fabricated PTEN-plasmid loaded lipid nanoparticles (PL-NANO) and ARV-825-loaded nanoliposomes (AL-NANO) to yield a mean particle size of less than 100 nm and greater than 99% encapsulation efficiency for each therapeutic payload. Combination of PL-NANO and AL-NANO displayed synergistic tumor growth inhibition and substantial apoptosis in in vitro two-dimensional and three-dimensional models. Importantly, simultaneous delivery of PL-NANO and AL-NANO achieved significant upregulation of PTEN expression levels and degradation of BRD4 protein to ultimately downregulate c-Myc levels in BRAFi-resistant melanoma cells. Altogether, lipid nanocarriers delivering this novel lethal cocktail stands as one-of-a-kind gene therapy to target undruggable c-Myc oncogene in BRAFi-resistant melanoma.

100 Deals associated with ARV-825

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hematologic Neoplasms	Preclinical	GB	University Of Dundee	08 Jun 2017
Hematologic Neoplasms	Preclinical	US	Medchemexpress LLC	08 Jun 2017
Solid tumor	Preclinical	GB	University Of Dundee	08 Jun 2017
Solid tumor	Preclinical	US	Medchemexpress LLC	08 Jun 2017

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