ARV-825 / Arvinas - LARVOL DELTA

Tumor microenvironment responsive nano-PROTAC for BRD4 degradation enhanced cancer photo-immunotherapy. (PubMed, Biomaterials) - "Herein, a nano-PROTAC formulation (ARV@PEG-ICG) consisting of a phototherapeutic agent named indocyanine green functionalized polyethylene glycol (PEG-ICG) and a BRD4 degrader (ARV-825) was fabricated for cancer photo-immunotherapy...The distant tumor growth can also be inhibited due to the activation of long-term immune response. Overall, the current study aims to combine typical PROTAC with functional nanomaterials to form nano-PROTAC with high performance for PROTAC delivery mediated cancer treatment."

Biomarker • IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2L1 • BRD4

Targeting Myc through BET-PROTAC elicits potent anti-lymphoma activity in diffuse large B cell lymphoma. (PubMed, Invest New Drugs) - "Notably, ARV-825 was more effective at downregulating c-Myc and BET protein levels than JQ1 in both in vitro and in vivo experiments. These evidences suggest that BET-PROTACs may offer a promising novel strategy for the clinical treatment of DLBCL."

Journal • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • ANXA5 • MYC

Anti-tumor effects following BET inhibition in preclinical models of pediatric and AYA osteosarcoma (AACR 2025) - "Effect of BETi (AZD5153, BMS-986378, ZEN-3694) in clinical trials for pediatric and adult solid tumors were investigated...To interrogate mechanisms of action, RNA-seq analysis of BET/BRD4 inhibition via AZD5153, PROTAC (ARV-825), and BRD4 siRNA in OS cell lines revealed distinct and overlapping patterns of alterations in gene expression...At the transcript level, increased DHRS2 was evident with no changes in TMPRSS9. These data sets reveal the promise of BETi for treatment of OS PDX derived from treatment naïve patients some of which go on to relapse, and in OS PDX derived from metastatic sites."

Preclinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • BRD2 • BRD4 • DHRS2 • H2AX

Development and optimization of a high-throughput LC-MS/MS method for the simultaneous determination of Exatecan and its Cathepsin B-sensitive prodrug, and ARV-825 in rat plasma: Application to pharmacokinetic study. (PubMed, J Pharm Biomed Anal) - "The proposed robust and economical method will be an alternative bioanalytical procedure for Exatecan and ARV-825 in the future. What is more, the present work could provide a reference for the clinical combination of the two drugs."

Journal • PK/PD data • Preclinical • Oncology • Targeted Protein Degradation • CTSB

A pH-responsive PROTAC-based nanosystem triggers tumor-specific ferroptosis to construct in situ tumor vaccines. (PubMed, Mater Today Bio) - "The selected PROTAC drug (ARV-825) can specifically degrade BRD4 without harming immune cells...Together with the PD1 antibody, this further enhanced the anti-tumor response of the in situ tumor vaccine and reversed the suppressive immune microenvironment. This antigen capture system provides a novel strategy to improve the anti-tumor efficacy of in situ tumor vaccines."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • BRD4 • GPX4

Targeting BRD4 ameliorates experimental emphysema by disrupting super-enhancer in polarized alveolar macrophage. (PubMed, Respir Res) - "This study suggested that downregulation of BRD4 might suppress airway inflammation and emphysema through disrupting the SEs of IRF4 and alveolar macrophages polarization, which might be a potential target of therapeutic intervention in COPD. A diagram of the mechanism by which BRD4 mediated super-enhancer of IRF4 in M2 AMs. Graphic illustration showed targeting BRD4 in M2 polarized AMs lead to the downregulation of MMP12 expression, resulting in the amelioration of experimental emphysema by disrupting the super-enhancer of IRF4."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Pulmonary Emphysema • Respiratory Diseases • BRD4 • IRF4

Construction of novel magnetic systems for cancer immunotherapy via cancer-immunity cycle circuits. (PubMed, J Control Release) - "MCM nanoparticles (magnetic nanoclusters coated with calcium-doped manganese carbonate) efficiently load the tumor-targeting drug PROTAC (ARV-825), enhancing its bioavailability, leading to specific degradation of BRD4 in tumor cells, and releasing a large number of tumor-associated antigens...Magnetic M-BMDCs introduced at the tumor site are attracted to these magnetized vaccines, resulting in a significant increase in antigen uptake and activation of DCs, significantly enhancing the tumor immune cycle. This co-administration strategy of magnetized vaccines and magnetized BMDCs provides a unique combination therapy for reversing immunosuppressive TEM and enhancing the efficacy of tumor immunotherapy."

Journal • Oncology • Targeted Protein Degradation • BRD4

Bromodomain-containing protein 4 Mediates TGF-β-induced Smooth Muscle Cell Differentiation (AHA 2024) - "Interestingly, the BRD4 inhibitor JQ1 and degrader ARV-825 effectively blocked the differentiation of 10T1/2 cells towards SMCs induced by TGF-β, as indicated by decreased induction of SMC markers such as SM22α and α-SMA. In addition, BRD4 mediates the binding between TAZ and Smad3 to regulate the SMC marker gene transcription. Take together, our findings suggest that BRD4 modulates TGF-β-induced SMC differentiation and might play a role in SMC differentiation-related vascular diseases."

Atherosclerosis • Cardiovascular • Dyslipidemia • Fibrosis • Hypertension • Immunology • Oncology • BRD4 • SMAD3 • TAFAZZIN • TGFB1

Liposomes-mediated enhanced antitumor effect of docetaxel with BRD4-PROTAC as synergist for breast cancer chemotherapy/immunotherapy. (PubMed, Int J Pharm) - "ARV825, a bromodomain-containing protein 4 (BRD4)-PROTAC, has demonstrated the capacity to enhance the antitumor effect of the classic chemotherapeutic agent docetaxel (DTX)...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."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2 • BRD4 • PD-L1

BRD4 Degradation Enhanced Glioma Sensitivity to Temozolomide by Regulating Notch1 via Glu-Modified GSH-Responsive Nanoparticles. (PubMed, Adv Sci (Weinh)) - "ARV-825 may play a role in modulating drug resistance by degrading the BRD4 protein, thereby exerting anti-glioma effects. Furthermore, mechanistic exploration revealed that T+A@Glu-NPs degraded the BRD4 protein, leading to the downregulation of Notch1 gene transcription and the inhibition of the Notch1 signaling pathway, thereby augmenting the therapeutic efficacy of glioma chemotherapy. Taken together, the findings suggest that T+A@Glu-NPs represents a novel and promising therapeutic strategy for glioma chemotherapy."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • BRD4 • NOTCH1

Targeted nanoliposomes of oncogenic protein degraders: Significant inhibition of tumor in lung-cancer bearing mice. (PubMed, J Control Release) - "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."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • Targeted Protein Degradation • BRD4 • KRAS • MYC

Novel gene therapy for drug-resistant melanoma: Synergistic combination of PTEN plasmid and BRD4 PROTAC-loaded lipid nanocarriers. (PubMed, Mol Ther Nucleic Acids) - "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."

Gene therapy • Journal • Gene Therapies • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • BRD4 • MYC • PTEN

Unlocking the Potential of Camel Milk-Derived Exosomes as Novel Delivery Systems: Enhanced Bioavailability of ARV-825 PROTAC for Cancer Therapy. (PubMed, Pharmaceutics) - "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."

Journal • Oncology • Targeted Protein Degradation • BRD4

Ultrasound Controllable Release of Proteolysis Targeting Chimeras for Triple-Negative Breast Cancer Treatment. (PubMed, Biomater Res) - "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."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • BRD4

Tuning the properties of polyphosphoester colloids for 31P magnetic resonance imaging and theranostics (ACS-Fall 2024) - "Moreover, due to amphiphilic character of gradient copolymers, the micelles can stabilize hydrophobic payload, simultaneously acting as drug delivery agents. Here, we encapsulated a potent anti-cancer, protein-degrading drug PROTAC (ARV-825), and studied the effect of polymer properties of drug encapsulation and release.In summary, we developed unique polyphosphonate gradient copolymer micelles that enable 31P MRI and delivery of therapeutics."

MRI • Cardiovascular • Oncology • Targeted Protein Degradation

BRD4 Is a Novel Regulator of Pleural Mesothelial to Mesenchymal Transition (ATS 2024) - "Pharmaceutical inhibitors of BRD4 (JQ1 and ARV-825) and small interfering RNA (siRNA) were used to manipulate BRD4 function/expression in HPMCs. The findings from the present study suggest that BRD4 is involved in the regulation of MesoMT and may potentially contribute to the development of PF. Keywords: BRD4, TGF-β, pleural mesothelial cell, pleural fibrosis, inhibitor"

Fibrosis • Immunology • Infectious Disease • Pneumococcal Infections • Pneumonia • Pulmonary Disease • Respiratory Diseases • BRD2 • BRD3 • BRD4 • TGFB1

BRD4 protein degradation for p53 mutant diffuse intrinsic pontine glioma (DIPG) via various delivery approaches for ARV-825 by using camel milk exosomes (AACR 2024) - "The results of the present study suggest the possibility of using CME as a viable delivery strategy for ARV-825 against DIPG. Further in vitro and in vivo studies are currently undergoing to validate the results and understand kinetics and the molecular mechanisms of ARV-825 loaded CME."

Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor • BRD4 • TP53

BET inhibitor increases DNA damage, modulates Wnt signaling, and suppresses osteosarcoma growth in naïve and metastatic disease models (AACR 2024) - "Combination index and Bliss independence analyses of bivalent BET inhibitor (BETi) AZD5153 or PROTAC ARV825 in combination with salvage agents demonstrated additive-to-synergistic cell growth inhibition in OS lines. TT2 PDX was resistant to commonly used salvage agents ifosfamide and irinotecan; however, combination BETi+ topotecan increased the probability of survival compared to each agent alone (p<0.05) and was well tolerated. These data collectively suggest that BET inhibition alone or in combination with low-dose salvage therapy holds promise as novel treatment strategies in aggressive OS."

Metastases • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • EPHA2 • EPHA4 • TCF7 • TXNIP

Targeting BRD4 with PROTAC degrader ameliorates LPS-induced acute lung injury by inhibiting M1 alveolar macrophage polarization. (PubMed, Int Immunopharmacol) - "Our study suggested that targeting BRD4 using ARV-825 is a potential therapeutic approach for ALI."

Journal • Acute Lung Injury • Inflammation • Respiratory Diseases • Targeted Protein Degradation • BRD4 • IRF7

inhibition of Cdk4/6 and Xpo1 induces Senescence with Acquired Vulnerability to Crbn-Based Protacs (APASL 2024) - "Through a senolytic-drug screen, CRBN-based PROTAC ARV-825 was identified as an agent that can selectively kill senescent liver cancer cells... 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."

Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor • Targeted Protein Degradation • CDK4 • CRBN • RB1

Bromodomain Protein-directed Agents and MYC in Small Cell Lung Cancer. (PubMed, Curr Cancer Drug Targets) - "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."

Journal • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • Targeted Protein Degradation • ASCL1 • BRD4 • RB1 • TP53

Dual inhibition of CDK4/6 and XPO1 induces senescence with acquired vulnerability to CRBN-based PROTAC drugs. (PubMed, Gastroenterology) - "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."

Journal • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CDK4 • CRBN • RB1

ARV-825 Showed Antitumor Activity against BRD4-NUT Fusion Protein by Targeting the BRD4. (PubMed, J Oncol) - "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."

Journal • Breast Cancer • Lung Cancer • NUT Midline Carcinoma • Oncology • Small Cell Lung Cancer • Solid Tumor • Targeted Protein Degradation • BRD4 • CRBN • GADD45G • NUTM1

CRISPR screening identifies BET and mTOR inhibitor synergy in cholangiocarcinoma through serine glycine one carbon. (PubMed, JCI Insight) - "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."

Journal • Biliary Cancer • Cholangiocarcinoma • CNS Disorders • Gastroenterology • Gastrointestinal Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • PHGDH • PSAT1

The Resistance Mechanism to BET-Protac in Multiple Myeloma (ASH 2023) - "AR1 and AR2 cells showed decreased sensitivity to ARV-825, MZ-1, OTX-015, I-BET151, Daunorubicin and Epirubicin...Combined use of ABCB1 inhibitors (verapamil, cyclosporin A, Elacridar) or knockout of ABCB1 could significantly reduce the IC50 of drug-resistant cells, increase the apoptosis rate after ARV-771 treatment, and increase the degradation of BRD4 and the down-regulation of c-Myc... Our results showed that BET-PROTAC resistance in MM cells wasindependent of β-catenin activation. The up-regulation of ABCB1 expression was the key mechanism mediating the resistance of myeloma cells to BET-PROTAC. C1orf112, CCDC167 and CRIP2 might be associated with drug resistance in myeloma and could affect prognosis, and their mechanisms in myeloma need to be further investigated."

Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • ABCB1 • BRD4 • DDR1 • MYC • TCF7