ARV-825

T-BEPRO revealed a particle size of 109.22 ± 0.266 nm with enhanced cellular uptake and activity. Remarkably, parenterally delivered T-BEPRO in tumor-bearing mice showed a substantially higher % tumor growth inhibition (TGI) of 77.6 % with long-lasting tumor inhibitory potential as opposed to individual drugs.

Patients suffering from BRAF mutant melanoma have tumor recurrence within merely 7 months of treatment with a potent BRAF inhibitor (BRAFi) like vemurafenib...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...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.

Cytotoxicity assays demonstrated potent anticancer activity, with IC50 values decreasing by 1.5 to 2-fold in cancer cell lines SF8628 DIPG and H1975R (resistant to Osimertinib). Distribution studies confirmed absorption through the ileum. This research highlights the potential of CMEs as a promising delivery platform for ARV-825, enhancing its therapeutic efficacy and offering a novel approach to cancer treatment.

PROTAC (ARV-825)-encapsulated microbubbles, ARV-MBs, were developed for the efficacious treatment of TNBC in vitro and in vivo...Under ultrasound, ARV-MBs could play an effective antitumor effect by potentiating the ubiquitination and degradation of BRD4 in tumor. The current study may provide a new idea for promoting clinical translation of drug-loaded microbubbles and PROTAC, and offer a new efficacious therapeutic modality for TNBC.

Here, novel BET-directed Proteolysis Targeting Chimeras (PROTACs) are discussed that show high antiproliferative activity in SCLC. Particularly ARV825, targeting specifically BRD4, exhibits superior cytotoxic effects on SCLC cell lines and may become a valuable adjunct to SCLC combination chemotherapy.

Our study demonstrates a striking synergy in senescence induction of liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy.

Through the induction of BRD4 protein degradation, ARV-825 can successfully limit BRD4-NUT 3T3 cell proliferation in vitro and in vivo. These findings suggested that the BRD4 inhibitor ARV-825 would be an effective therapeutic strategy for treating NUT carcinoma that with the genetic feature of BRD4-NUT fusion event.

To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anti-cancer synergy when combined with genetic ablation of members of the mTOR pathway...Knockdown of PSAT1 was sufficient to replicate synergy with single agent inhibition of either BET or mTOR. Our results tie together epigenetic regulation, metabolism, and apoptosis induction as key therapeutic targets for further exploration in this underserved disease.

ARV-825 (ARV) was employed as a BRD4 targeted PROteolysis TArgeting Chimera that selectively degrades the BRD4 to downregulate c-Myc. Histopathological analysis revealed significant tumor necrosis and downregulation of Ki-67 and BRD4 protein in vivo. Promising in vivo antitumor activity and prolonged survival demonstrated by NANOVB signifies its clinical translational potential for BRAFi-resistant melanoma.

The results show the first evidence of the essential role of the BRD4/nuclear PD-L1/RelB axis in breast CSC formation. The nuclear PD-L1 regulates RelB, and the RelB/p65 complex induces IL6 and breast CSC formation. Targeting nuclear PD-L1 represents a potential and novel tool for immunotherapies of intractable BC. Video Abstract.

Promisingly, in vitro MDM2 inhibition with Idasnutlin and TP53 reactivation via Eprenetapopt was able to renew TNFRSF10B protein expression. Additionally, applying the BRD4-degrading PROTAC ARV-825 and the CDK4/6 inhibitor Abemaciclib as single-agents and in synergistic combination significantly reduced TP53-altered DLBCL cell line viability. Our analysis presents key associations within a genomic network of actionable targets capable of providing clarity within the evolving precision CAR-T treatment landscape.

ARV-825 was effective in both p53 wild-type (WT) breast tumor cells and in cells lacking functional p53 either alone or in combination with tamoxifen, while the effectiveness of ABBV-744 was limited to fulvestrant plus palbociclib in p53 WT cells. These differential effects may be related to the capacity to suppress c-Myc, a downstream target of BRD4.

CDK4/6i-induced senescent cells were highly sensitive to the senolytics ARV-825 (LNCaP SI=11.03; 22Rv1 SI=7.11) and Navitoclax (LNCaP SI=7.01). However, the senescent phenotype is reversible upon drug withdrawal and re-induction of senescence upon drug re-exposure is poor. Hence, our results highlight the importance of eliminating PC senescent cells at first occasion and could lead to repurposing CDK4/6 inhibition in prostate cancer.

Through a senolytic-drug screen, CRBN-based PROTAC ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells...Mechanistically, USP2 directly interacts with CRBN, leading to the deubiquitination and stabilization of CRBN in senescent liver cancer cells.ConclusionOur study demonstrates the striking synergy of inducing senescence in liver cancer cells through the combination of CDK4/6 inhibitor and XPO1 inhibitor. These findings also shed light on the molecular processes underlying the vulnerability of senescent liver cancer cells to CRBN-based PROTAC therapy and suggest a potential therapeutic strategy for liver cancer treatment.

In addition, several BRD4 inhibitors have been evaluated for therapeutic purposes as monotherapy or in combination with chemotherapy, radiotherapy, and immune therapies. Here, we provide a critical appraisal of studies evaluating various BRD4 inhibitors and degraders as novel treatment strategies against GBM.

Treatment with PROTAC ARV825 that degrades BET proteins, resulted in similar growth inhibitory effects...Combination treatments of BETi+topotecan/ifosfamide indicated that AZD5153 potentiated the anti-cancer effect of salvage therapy in TT2 OS PDX, was well tolerated, and increased the probability of survival in mice. Efficacy in an OS RS+ metastatic lesion model is in progress. These data collectively suggest that BET inhibition as a single agent and in combination with low-dose salvage therapy holds promise as novel treatment strategies for inducing RS-mediated cell death in aggressive OS.

We observed the up-regulated expression of BRD4 in colorectal cancer (CRC) after doxorubicin (DOX) treatment, which might be a potential mechanism for DOX resistance. Taken together, these data reveal that ARV-825 can heighten DOX sensitivity in CRC treatment and BRD4 is a potential therapeutic target for DOX-resistant CRC. The ARV-DOX/cRGD-P preparations have outstanding anti-cancer effects and may be used for clinical treatment of colorectal cancer in the future.

In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis and demonstrated efficacy in resistant RB deficient cell lines. These studies indicate that administration of BET inhibitors/degraders, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients and may further prolong progression-free survival.

The BRD4 bromodomain protein has emerged as an actionable target in recent years given its role orchestrating numerous oncogenic processes that drive aggressive DLBCL capable of rejecting R-CHOP regimens. Our results suggest that increased BRD4 expression alongside TP53 alterations are associated with EFS24 failure, a cold immune microenvironment, and the loss of critical tumor suppressors, namely CDKN1A. We assayed the BRD4-degrading PROTAC ARV-825 vs. cell line models and are the first to report the substantial preclinical efficacy of this molecule in DLBCL.

Herein, we proposed a combined treatment strategy based on Cyclo (Arg-Gly-Asp-d-Phe-Lys) (cRGDfk) peptides-modified nanoparticle named cRGD-P in a self-assembly method for the co-delivery of doxorubicin (DOX) and BRD4 PROTAC degrader ARV-825 (ARV). The cRGD-P/ARV-DOX system could effectively suppress the heterotopic and orthotopic growth of glioma by increasing tumor apoptosis, inhibiting tumor proliferation, and decreasing tumor angiogenesis in vivo. Therefore, the cRGD-modified nanoparticle to co-deliver DOX and ARV provides a potential platform for exploiting a more effective and safer combination therapy for glioma.

Subsequently, released drug engenders antitumor effect via attenuating cells proliferation, inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6, STAT3 and AKT. Taken together, our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma, which may provide a novel strategy for glioma therapy in future.

Moreover, secondary transplantation from PDX and ΔPTEN models of T-ALL, confirmed delayed leukemia development and extended survival of mice engrafted with T-ALL from ARV-825 treated mice, providing functional confirmation of depletion of LICs. Hence, BRD4 degradation is a promising LIC-targeting therapy for T-ALL.

AP-NLC. Higher amount of red fluorescence throughout the spheroid surface further confirmed superior efficacy of AP-NLC in tumor penetration and cell killing.

This research deals with the development of asialoglycoprotein receptors (ASGPR) directed nanoliposomes incorporating a novel BRD4 (Bromodomain-containing protein 4) protein-targeted PROTAC (Proteolysis Targeting Chimera), ARV-825 (ARV) (GALARV), and to investigate the anticancer efficacy of GALARV for specific delivery in hepatocellular carcinoma...Notably, GALARV treatment resulted in significant apoptosis and subsequent inhibition of the cell viability of 3D tumor spheroids of hepatocellular carcinoma. These results suggest that GALARV is a novel actively targeted PROTAC-based nanotherapeutic approach for hepatocellular carcinoma.

ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.

Introduction: New Diffuse Large B-cell (DLBCL) treatments remain a clinical need despite the success of rituximab combined with CHOP chemotherapy (RCHOP), which results in durable responses in 60-70% of patients...Lasty, 4 DLBCL cell lines were assayed against the BRD4 PROTAC ARV-825, Venetoclax, and inhibitors of epigenetic regulation... Our results indicate that distinct genomic groups exist within rrDLBCL, that TP53 alterations strongly associate with the EZB-enriched group, and that if TP53 alterations continue to predict poor CAR-T response, these tumors may be susceptible to BRD4 inhibition. Our observations indicate a significant climb in TP53 association with EZB tumors and their matched alterations after rrDLBCL transition in comparison to the pre-treatment landscape. Enrichment may indicate that EZB-like tumors lack some of the tools necessary to make the transition to advanced disease but provide an ideal environment for the acquisition of TP53 alterations.

A novel treatment strategy by co-targeting c-Myc and tumor stroma was explored in vemurafenib-resistant melanoma. Tumor growth inhibition in 3D spheroids with reduction of TGF-β1 was observed with ARNIPL treatment. Therefore, ARNIPL could be a promising therapeutic approach for the treatment of vemurafenib-resistant melanoma.

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.

Bromodomains and extra-terminal (BET) protein inhibitors, such as JQ1 and ARV-825, are promising cancer therapeutic agents that can be used by targeting c-Myc. Furthermore, JQ1 restrained the glycolysis of B-ALL cell lines by remarkably downregulating the rate-limiting enzymes of glycolysis, such as hexokinase 2, phosphofructokinase, and lactate dehydrogenase A. Moreover, the cell cycle arrest was reversed in B-ALL cells with overexpressed c-Myc treated by JQ1, which is involved in the enhancement of glycolysis. CONCLUSIONS The BET inhibitor JQ1 suppresses the proliferation of ALL by inhibiting c-Myc-mediated glycolysis, thus providing a new strategy for the treatment of ALL.

In the NB xenograft model, ARV-825 profoundly reduced tumor growth and led to the downregulation of BRD4 and MYCN expression in mice. Taken together, these findings provide evidence that PROTAC BET inhibitor is an efficient way to achieve MYCN/c-Myc manipulation, and ARV-825 can be used as a potential therapeutic strategy for the treatment of neuroblastoma.

In a recent study, Saraswat and colleagues identified a novel proteolysis targeting chimera (PROTAC), ARV-825 (ARV), that efficiently degrades bromodomain-containing protein 4 (BRD4) to drug the 'undruggable' MYC in pancreatic cancer. ARV-loaded polyethylene glycol-poly lactic acid-co-glycolic acid (PLGA-PEG) polymeric nanoparticles (ARV-NPs) showed promising anticancer activity in both 2D cell culture and 3D multicellular tumor spheroid models of pancreatic cancer. This study demonstrates a unique therapeutic strategy in which targeting BRD4 for degradation via the E3 ubiquitin ligase cereblon (CRBN) pathway leads to sustained inhibition of oncogenic MYC expression for effective treatment of pancreatic cancer.

Aim: To explore the anticancer activity of a novel BRD4 protein degrader ARV-825 (ARV) and its nanoformulation development (ARV-NP) for treatment of pancreatic cancer...Most importantly, ARV-NP treatment significantly inhibited the cell viability of 3D tumor spheroids of pancreatic cancer. ARV-NP represents a novel therapeutic strategy for pancreatic cancer.

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 in vitro and in vivo.