ARV-825 / Arvinas - LARVOL DELTA

Discovery of highly potent and efficacious Bromodomain and Extra-terminal (BET) degraders with activity against acute myeloid leukemia and triple-negative breast cancer. (PubMed, Eur J Med Chem) - "Through structural optimization, 36 (F364) was identified as a potent BRD4 degrader, exhibiting a Dmax of 93.96% and a DC50 of 0.676 nM in the HiBiT assay using HEK293-BRD4-HiBiT-KI cells, slightly superior to the positive control ARV-825. This compound showed strong antiproliferative activity in MV4-11 cells (IC50 = 4.99 nM) and displayed marked efficacy against SHP099-resistant MV4-11 cells (IC50 = 1.62 nM), indicating its potential to overcome resistance to SHP2 inhibitors...In xenograft mouse models using MV4-11 and MDA-MB-231 cells, F364 demonstrated significant antitumor efficacy without observable toxicity. In summary, F364 has been identified as a novel and potent BRD4 degrader, showing promising therapeutic potential for the treatment of acute myeloid leukemia and triple-negative breast cancer."

Journal • Acute Myelogenous Leukemia • Breast Cancer • Hematological Malignancies • Immunology • Leukemia • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRD4 • CRBN

Exosome-Mediated Delivery of PROTACs for Targeted Protein Degradation in Cancer, Neurodegenerative, Infectious, and Inflammatory Diseases. (PubMed, J Cell Mol Med) - "Proof-of-concept studies, such as camel milk-derived exosomes delivering the BRD4-targeting PROTAC ARV-825, demonstrate enhanced permeability, lower IC50 values, and improved oral bioavailability. Finally, we discuss key hurdles to clinical translation: scalable production, purification, and standardization, and outline future directions for exosome-mediated targeted protein degradation."

Journal • Review • CNS Disorders • Infectious Disease • Oncology • Targeted Protein Degradation • BRD4

Optimized pH-Responsive Crosslinked PROTAC Nanoparticles Enable Systemic Therapy and Survival Benefit in Orthotopic Glioblastoma and Pancreatic Cancer Models (EACR 2026) - "A panel of PROTACs (ARV825, LC2, ARV471, QC-01-175 and others) was screened, and formulations were optimized using particle size/dispersity, serum stability, and encapsulation efficiency...Hydrophobic payloads (approximately logP > −1) were broadly encapsulated, whereas a highly water-soluble PROTAC (lenalidomide) loaded poorly, defining a practical encapsulation boundary for this platform... pH-responsive crosslinked nanoparticles can convert PROTACs into systemically deliverable therapeutics with improved efficacy and safety signals in hard-to-treat solid cancers. This platform provides actionable design rules (payload physicochemical window and linker/formulation tuning) to accelerate translational targeted protein degradation therapy."

Preclinical • Brain Cancer • Glioblastoma • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation

Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance (AACR 2026) - "Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263- and ARV825-induced senolysis, reducing tumour growth and metastasis. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263- and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies."

Clinical • Late-breaking abstract • Oncology

Harnessing combinatorial nanomedicine for simultaneous BRD4 degradation and stromal disruption against pancreatic ductal adenocarcinoma (AACR 2026) - "To overcome pharmacokinetic barriers, we designed a dual-route nanomedicine platform: oral self-nanoemulsifying PND-1186 (PNDnano, FAK inhibitor) and intravenous albumin-anchored ARV-825 nanoliposomes (AAnano, BRD4 PROTAC). This dual-targeting approach provides robust antitumor efficacy without systemic toxicity, addressing a critical unmet need in PDAC treatment. This strategy that simultaneously disrupts stromal barriers and eliminates oncogenic drivers, transcending conventional chemotherapy limitations and providing a translational framework for treating desmoplastic malignancies."

Stroma • Oncology • Pancreatic Ductal Adenocarcinoma • BRD4

Proximity Binding Assay for PROTAC Ternary Complex Analysis. (PubMed, ACS Sens) - "The assay is applied to cereblon (CRBN) and von Hippel-Lindau (VHL) as E3 ligase substrate receptors, a range of compounds including AT1, MZ1, dBETs, and ARV-825 as PROTACs, and the two bromodomains of BRD2, BRD3, BRD4, and BRDT proteins as targets. Automated workflows enable the measurement of 384 real-time sensorgrams in a single run using picomole sample quantities. The insights into proximity-mediated binding kinetics can enable the development of PROTACs and molecular glues with improved properties for targeted protein degradation."

Journal • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • BRD2 • BRD3 • BRD4 • BRDT • CRBN

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

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

MYC Addiction as a Targetable Vulnerability in Nelarabine-Resistant T-Cell Acute Lymphoblastic Leukemia. (PubMed, Cancer Sci) - "Consistent with a MYC-driven mechanism, treatment with ARV-771 and ARV-825 induced potent degradation of BET proteins, suppressed MYC transcription, and profoundly impaired the viability and proliferation of nelarabine-resistant cells. Yes, approved number: IRB Approval No.: Med-Ethics [2026] IIT No. (19)."

Journal • Acute Lymphocytic Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Psychiatry • T Acute Lymphoblastic Leukemia • T-cell Acute Lymphoblastic Lymphoma

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."

P53mut • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Glioma • Oncology • Solid Tumor • BRD4 • TP53

Addressing the Release and Permeation Challenges of High-Tg Drugs in Amorphous Solid Dispersions. (PubMed, Mol Pharm) - "Ivacaftor and ARV-825 were selected as model drugs and were formulated as ASDs with hydroxypropyl methylcellulose acetate succinate (HPMCAS). Addition of glyceryl tributyrate, while increasing the release rate, decreased the permeation rate due to formation of larger droplets. In conclusion, the addition of a plasticizer to an ASD containing a high Tg drug led to an improvement in release rate but increased the size of drug-rich nanodroplets produced via the release process with unknown potential implications for in vivo performance."

Journal

Quantitative analysis of ternary complex kinetics by a surface immobilization method. (PubMed, Biochem Biophys Res Commun) - "Application to the CRBN/ARV-825/BRD4 system reveals strong positive cooperativity (α = 175), which correlates with exceptional degradation potency. Our approach provides a systematic methodology for quantifying ternary complex kinetics and offers a robust platform for rational degrader optimization through kinetic-guided design."

Journal • Targeted Protein Degradation • BRD4 • CRBN

Viability of Dugesia dorotocephala Planaria with the Senolytic Drug ARV-825. (PubMed, MicroPubl Biol) - "This demonstrated a concentration-dependent reduction in viability, 91.7% survival with 1µM ARV-825 reduced to 25% survival in 10 µM ARV-825. This suggests ARV-825 has an effect on Dugesia dorotocephala , and indicates that this may be a suitable model organism for studying ARV-825."

Journal • Targeted Protein Degradation • BRD4

A versatile self-adjuvanting macro-microporous ZIF-8@Mn MOF platform for efficient antigen capture and presentation to boost antitumor immunity. (PubMed, J Control Release) - "Here, we develop a novel ISTV platform (SOM-ZIF-8@Mn/ARV) integrating a specific ICD inducer (ARV-825), and a multifunctional antigen catcher (SOM-ZIF-8@Mn) to boost antitumor immunity...This ISTV platform triggers robust antitumor immunity and achieves significant tumor growth inhibition when combined with αPD-1 blockade. The SOM-ZIF-8@Mn/ARV platform represents a powerful and effective advancement in improving the antitumor immune efficiency of ISTVs, offering a straightforward approach to the challenges faced in tumor immunotherapy."

Journal • Oncology • Targeted Protein Degradation • BRD4 • CD8

Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance. (PubMed, Nat Aging) - "Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro, and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263-induced and ARV825-induced senolysis, reducing metastasis and tumor growth. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263-induced and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies."

Journal • Oncology

Therapeutic Potential of Bovine Colostrum- and Milk-Derived Exosomes in Cancer Prevention and Treatment: Mechanisms, Evidence, and Future Perspectives. (PubMed, Pharmaceuticals (Basel)) - "ARV-825-CME formulations increased antitumor activity in some cancer types...However, significant challenges remain in terms of their large-scale isolation, load heterogeneity, and regulatory standardization. Consequently, BMEs represent a new generation of biogenic nanoplatforms at the intersection of nutrition, immunology, and oncology, paving the way for innovative therapeutic approaches."

Journal • Review • Breast Cancer • Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Ginsenoside Rh2- functionalized liposomes enhanced BRD4-PROTAC delivery and antitumor efficacy via improved tumor targeting and ECM remodeling. (PubMed, Mater Today Bio) - "ARV825, a BRD4-targeting PROTAC, exerts potent antitumor effects by degrading BRD4, thereby suppressing Bcl-2 and PD-L1 expression, inducing apoptosis, and enhancing T cell-mediated immunity...As a result, ARV@Gip exhibited superior antitumor efficacy through dual mechanisms, including enhanced apoptosis and immune activation, outperforming ARV@lip in both tumor models. Collectively, this GRh2-functionalized liposomal platform overcomes key pharmacological barriers by integrating enhanced tumor targeting, ECM modulation, and dual pro-apoptotic/immunostimulatory effects, offering a promising therapeutic strategy for breast cancer."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BCL2 • BRD4 • SLC2A1

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 • MYC • TCF7

Proteolysis targeting chimeras as senolytics: An emerging senotherapy for combating aging. (PubMed, J Pharmacol Exp Ther) - "Recent efforts have led to the development of several senescence-targeting proteolysis targeting chimeras, including ARV825, PZ15227, 753B, Gal-ARV-771, and Gal-MS99, which exhibit selective senolytic activity and improved safety and efficacy profiles when compared with small molecule inhibitors...PROteolysis TArgeting Chimeras (PROTACs) that induce selective degradation of target proteins, are emerging as a promising therapeutic strategy to address this unmet medical need. Recently, PROTACs have been explored as novel senolytics-termed "SenoTACs," which display improved safety and efficacy in targeting senescent cells for fighting aging-related diseases."

Journal • Review • Oncology • Targeted Protein Degradation

Microfluidic-assisted preparation of ARV 825 and Osimertinib loaded liposomal formulation as a potential system for colorectal cancer therapy. (PubMed, Int J Pharm) - "3D printed T-junction chips could be a promising alternative for the preparation of liposomes. The microfluidic-assisted co-delivery of ARV and OSI in liposomal formulations represents a compelling approach to overcoming drug resistance and enhancing CRC therapy by concurrently targeting EGFR and BRD4."

Journal • Colorectal Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BRD4

Effectiveness of PROTAC BET degraders ARV-825 and ARV-771 in combating chemoresistance in HNSCC (AACR-NCI-EORTC 2025) - "Previous studies in our lab displayed that cisplatin-induced senescent HN30 HNSCC cells are sensitized to cell death via ABT-263 (Navitoclax), a senolytic BCL-2/BCL-XL dual inhibitor. The BET degraders ARV-825 and ARV-771 successfully sensitized chemoresistant head and neck cancer cells to cisplatin treatment. This may be due to the downregulation of the proliferation and survival markers c-Myc and Survivin following BRD4 degradation. Increased gH2AX expression and downregulated RAD51 with ARV-825 treatment suggest that accumulated DNA damage may contribute to senescence and apoptosis induction due to impaired BRD4 function."

IO biomarker • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA5 • BCL2 • BCL2L1 • BIRC5 • BRD4 • MYC • RAD51

BRD4 Mediates Transforming Growth Factor-β-Induced Smooth Muscle Cell Differentiation from Mesenchymal Progenitor Cells. (PubMed, Int J Mol Sci) - "In addition, the BRD4 inhibitor JQ1 and degraders ARV-825 and dBET1 suppressed TGF-β-induced SMC marker gene expression. Interestingly, the knockdown of BRD4 also attenuated the induction of myocardin due to TGF-β in 10T1/2 cells. Taken together, this study demonstrates that BRD4 is a novel modulator for SMC differentiation from mesenchymal progenitor cells through the regulation of TAZ and myocardin."

Journal • BRD4 • SMAD3 • TAFAZZIN • TGFB1

Polymer-engineered PROTAC nanovehicles amplify synergistic effects with temozolomide by BRD4 degradation. (PubMed, Biomater Sci) - "Furthermore, the delivery of ARV-825 using NPs achieves synergistic anti-tumor effects with temozolomide (TMZ) in GBM cells. These findings validate nanovehicles as a strategic solution for PROTAC limitations and provide a blueprint for translating catalytic degradation into clinically viable therapies against GBM."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • Targeted Protein Degradation • BRD4

Oxygen-Generating Transdermal Nanoplatform Codelivering BRD4 Proteolysis-Targeting Chimera/Verteporfin/CaO2 Synergistically Remodels Immunosuppressive Melanoma Microenvironment to Potentiate Combination Immunotherapy. (PubMed, ACS Nano) - "Melanoma relapse and metastasis remain formidable clinical challenges, with the inadequate immunogenicity and highly immunosuppressive tumor microenvironment (ITME) presenting serious obstacles to current postsurgical immunotherapies. Moreover, ARV825 acts like a PD-L1 blocking agent, cooperatively inhibiting immune evasion and resistance. Notably, AV@LDL&CaO2 MNs achieved a 90.0% melanoma inhibition rate, and elicited robust systemic immune protection against recurrence and metastasis with low-dose administration and minimal toxicity, offering a self-managing and innovative photodynamic-epigenetic-metallo-immunotherapy strategy for efficient postoperative melanoma management."

Journal • Dyslipidemia • Gene Therapies • Melanoma • Oncology • Solid Tumor • Targeted Protein Degradation • BRD4

Discovery of a potent BRD4 PROTAC and evaluation of its bioactivity in breast cancer cell lines. (PubMed, Biochem Pharmacol) - "Referring to the design of ARV-825, ARV-771 and MZ1, two novel BRD4 PROTACs were rationally designed and prepared via connecting the pan-BET selective bromodomain inhibitor JQ1 and two universal E3 ligase ligands targeting Von Hippel-Lindau (VHL) and cereblon (CRBN), namely VHL-JQ1 and CRBN-JQ1. Furthermore, combination therapy studies revealed that VHL-Q1 exhibited antagonistic effects when combined with paclitaxel, while demonstrating synergistic effects with cisplatin in TNBC treatment. Overall, our findings highlight VHL-JQ1 as a promising chemical probe for investigating BRD4 biological functions and a potential therapeutic candidate for TNBC treatment."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • Triple Negative Breast Cancer • Von Hippel-Lindau Syndrome • BRD4 • CRBN • KRAS