ARCC-29 / Arvinas - LARVOL DELTA

Balancing Stability and Payload Release in Glutathione-Responsive PROTAC Prodrugs Targeting Prostate Cancer. (PubMed, JACS Au) - "To widen the therapeutic window, we designed a two-tier selective prodrug strategy enabling glutathione (GSH)-responsive and PCa-targeted delivery of the BET PROTAC MZ1 caged via a carbonate moiety...This structural feature may promote passive membrane permeability, which underscores the complexity of dual-targeting strategies. Collectively, our study establishes design principles for stable yet GSH-responsive carbonate-disulfide prodrugs and provides a framework for the rational development of PROTAC prodrugs, emphasizing the importance of coordinated optimization of their individual components to achieve predictable biological behavior."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation

Acquired temozolomide resistance drives a stem-like state in glioblastoma that is vulnerable to BET protein targeting (EACR 2026) - "The impact of BETi and TMZ, alone or in combination, as well as BET-PROTACs were evaluated by MTT, flow cytometry, and WB. Acquired TMZ resistance is associated with elevated BET proteins levels and a stem-like state in GBM models. Pharmacological inhibition and proteolytic degradation of BET proteins reduce viability and stemness features, supporting that TMZ-resistant cells exhibit increased BET dependence that can be therapeutically exploited."

IO biomarker • Brain Cancer • Glioblastoma • Glioma • Solid Tumor • Targeted Protein Degradation • BCL2 • BRD4 • SOX2 • SOX9

Deciphering the Ubiquitin-like Code of DNA-PK: Mechanisms and Therapeutic Opportunities. (PubMed, Biomolecules) - "From a translational perspective, we argue that the exceptional size of DNA-PKcs (~470 kDa) and its topological entrapment on DNA render it an unusually challenging PROTAC target-one that may require p97/VCP-assisted extraction before proteolysis can proceed. We also highlight the underappreciated risk that E3 ligase loss-of-function, already documented in BET-PROTAC resistance, may similarly undermine DNA-PKcs degrader strategies."

Journal • Review • Targeted Protein Degradation • HUWE1

Design and evaluation of selective BET PROTACs with potent antitumor efficacy and safety against acute myeloid leukemia. (PubMed, Eur J Med Chem) - "In this work, we designed and synthesized a series of novel BET PROTACs based on the clinical inhibitor ABBV-075. The favorable efficacy-safety balance of A10 underscores its strong potential as a preclinical candidate for AML therapy. This study highlights how rational PROTAC optimization can yield degraders with enhanced therapeutic windows, providing a promising path forward for targeted protein degradation in AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • CRBN

Semi-rigid linkers improve the pharmacokinetic properties and therapeutic efficacy of BET PROTACs for cancer therapy. (PubMed, Eur J Med Chem) - "Furthermore, CR10 significantly inhibited the growth of MV4-11 and A549 xenograft tumors at a dose as low as 2 mg/kg, without apparent toxicity. This semi-rigid linker-containing degrader represented a promising new mechanism-based candidate for the treatment of hematologic malignancies and lung cancer, warranting further investigation."

Journal • PK/PD data • Hematological Disorders • Hematological Malignancies • Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • BRD2 • BRD3 • BRD4

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

Tuna Collagen-Based hydrogels for the targeted delivery of BET inhibitors and BET-PROTACs in breast cancer therapy. (PubMed, Eur J Pharm Biopharm) - "Targeted protein degradation (TPD) strategies, including BET inhibitors and PROTACs, offer a promising approach for cancer therapy by selectively degrading disease-relevant proteins. Cell cycle arrest and apoptosis assays, together with Synchrotron FTIR microspectroscopy, confirmed preservation of the drugs' mechanisms of action. To our knowledge, this is the first study integrating JQ1 and MZ1 into a natural gelatin-based hydrogel system for localized cancer therapy, providing a foundation for in vivo evaluation and potential applications in advanced drug delivery, tissue engineering, and precision medicine."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Topical BET PROTACs for locally restricted protein degradation in the lung. (PubMed, RSC Med Chem) - "In contrast to the significant knowledge that has been generated for the design of oral PROTACs, there is little expertise regarding inhaled and generally topically administered PROTACs. In this work we (1) introduce parameters influencing the inhaled route of administration of PROTACs and (2) describe the first examples of inhaled bromodomain and extra terminal domain (BET) PROTACs which were designed for inhaled delivery and characterized in vitro and in vivo."

Journal • Targeted Protein Degradation

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

Evaluation of Cereblon-Directing Warheads for the Development of Orally Bioavailable PROTACs. (PubMed, J Med Chem) - "We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall in vitro degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor in vivo pharmacokinetic profile. To further demonstrate the PG utility, we describe here optimization efforts that led to the discovery of an orally bioavailable BET-PROTAC SJ44236 (8), and results of a comprehensive in vitro/vivo comparative study with analogues containing alternative CRBN-directing warheads. Our study highlights the importance of considering warhead modifications when optimizing PROTACs for oral delivery."

Journal • Targeted Protein Degradation • CRBN

THE BET PROTAC INHIBITOR GNE-987 DISPLAYS ANTI-TUMOR EFFECTS BY TARGETING SUPER-ENHANCERS REGULATED GENE IN OSTEOSARCOMA (SIOP 2024) - "GNE-987 selectively degraded BRD4 and disrupted transcriptional regulation of oncogenes in OS. GNE-987 has the potential to influence KRT80 against OS."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor • Targeted Protein Degradation • BRD4 • KRT80

The BET PROTAC inhibitor GNE-987 displays anti-tumor effects by targeting super-enhancers regulated gene in osteosarcoma. (PubMed, BMC Cancer) - "This research revealed that GNE-987 selectively degraded BRD4 and disrupted the transcriptional regulation of oncogenes in OS. GNE-987 has the potential to affect KRT80 against OS."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • Targeted Protein Degradation • BRD4 • KRT80

BRD4-targeting PROTACs Synergize With Chemotherapeutics Against Osteosarcoma Cell Lines. (PubMed, Anticancer Res) - "The study suggests that the application of novel BET PROTACs in combination with chemotherapeutics could represent a new therapeutic option to improve the therapy of osteosarcomas. First orally available PROTACs have reached clinical trials."

Journal • Preclinical • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • Targeted Protein Degradation • AXL • BCL2L1 • BRD4 • CA9 • CDH1 • HER-2 • VIM

Intratracheal administration of a PROTAC with subnanomolar potency induces BRD4 degradation in the lung without systemic target engagement (ERS 2023) - "PROTACs with subnanomolar potency were identified, showing a fast onset of action and FMT inhibition in vitro, while the PROTAC tested in vivo induced pronounced, dose-dependent BRD4 degradation in the central and peripheral lung with no signs of systemic target engagement. The results demonstrate that BET PROTACs have anti-fibrotic effects in vitro and an inhaled approach may provide efficacy in the lung without unwanted systemic effects.; Physiology; Pulmonary function testing; Cell and molecular biology; Imaging"

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • BRD4 • TGFB1

The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS-STING in response to light damage. (PubMed, J Neuroinflammation) - "This study indicates targeted degradation of BET by dBET6 exerts neuroprotective effects by inhibiting cGAS-STING in reactive retinal macrophages/microglia, and is expected to become a new strategy for treatment of retinal degeneration."

Journal • Age-related Macular Degeneration • Genetic Disorders • Inflammation • Inherited Retinal Dystrophy • Macular Degeneration • Ocular Inflammation • Ophthalmology • Retinal Disorders • Retinitis Pigmentosa • Targeted Protein Degradation • STING

BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications. (PubMed, Molecules) - "The design of bivalent BET inhibitors, kinase and BET dual inhibitors, BET protein proteolysis-targeting chimeras (PROTACs), and Brd4-selective inhibitors are discussed...Apart from single agent treatment alone, BET inhibitors have also been combined with other chemotherapeutic modalities for cancer treatment demonstrating favorable clinical outcomes. The investigation of specific biomarkers for predicting the efficacy and resistance of BET inhibitors is needed to fully realize their therapeutic potential in the clinical setting."

Journal • Review • Oncology • Targeted Protein Degradation • BRD2 • BRD3 • BRD4 • BRDT

From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors. (PubMed, Eur J Med Chem) - "An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib...In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development."

Journal • Brain Cancer • Hematological Malignancies • Leukemia • Medulloblastoma • Oncology • Solid Tumor • Targeted Protein Degradation • BRD2 • BRD4

BET inhibitors: an updated patent review (2018-2021). (PubMed, Expert Opin Ther Pat) - "In recent years, an increasing number of structurally diverse BET inhibitors have been identified, including pan BET inhibitors, BD1 or BD2 selective BET inhibitors, bivalent BET inhibitors, kinase and BET dual inhibitors and BET-PROTACs. Despite of many challenges, BET inhibitors have high potential in the treatment of cancer and other diseases and the development of next-generation BET inhibitors could be promising."

Journal • Review • Immunology • Inflammation • Metabolic Disorders • Oncology

MST and TRIC Technology to Reliably Study PROTAC Binary and Ternary Binding in Drug Development. (PubMed, Methods Mol Biol) - "In this chapter, we describe the application of MicroScale Thermophoresis (MST) and Temperature-Related Intensity Change (TRIC) to characterize both the binary and ternary binding of PROTACs with target proteins and ubiquitin ligases along with an efficient determination of the cooperativity of the ternary complex formation. The assay development and experimental procedure to characterize the well-described BET PROTAC MZ1 show how MST and TRIC can be applied as a fast and highly sensitive method for PROTAC discovery."

Journal • Targeted Protein Degradation

PD-L1 is upregulated via BRD2 in head and neck squamous cell carcinoma models of acquired cetuximab resistance. (PubMed, Head Neck) - "PD-L1 is significantly elevated in HNSCC models of acquired cetuximab and cisplatin resistance where BRD2 is the primary regulator."

IO biomarker • Journal • Head and Neck Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Targeted Protein Degradation • EGFR • PD-L1

Aptamer-PROTAC Conjugates (APCs) for Tumor-specific Targeting in Breast Cancer. (PubMed, Angew Chem Int Ed Engl) - "As proof of concept, the first aptamer-PROTAC conjugate (APC) was designed by conjugating a BET-targeting PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR) showed improved tumor targeting ability in a MCF-7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus, the APC strategy may pave the way for the design of tumor-specific targeting PROTACs and have broad applications in the development of PROTAC-based drugs."

Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

MZ1 co-operates with trastuzumab in HER2 positive breast cancer. (PubMed, J Exp Clin Cancer Res) - "We describe an active novel combination that includes the BET-PROTAC MZ1 and trastuzumab, in HER2+ tumors. Further studies should be performed to confirm these findings and pave the way for their future clinical development."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • HER-2

PROTACs: A Hope for Breast Cancer Patients? (PubMed, Anticancer Agents Med Chem) - "A novel innovation emerged around two decades ago that has great potential to not only overcome the limitations but also can provide future direction for the treatment of many diseases which has presently not many therapeutic options available and regarded as incurable with traditional techniques; that innovation is called PROTAC (Proteolysis Targeting Chimera) and able to efficaciously ubiquitinate and debase cancer encouraging proteins by noncovalent interaction. PROTACs are constituted of two active regions isolated by a linker and equipped for eliminating explicit undesirable protein. It is empowering greater sensitivity to "drug-resistant targets" as well as a more prominent opportunity to influence non-enzymatic function. PROTACs have been demonstrated to show better target selectivity contrasted with traditional small-molecule inhibitors. So far, the most investigation into PROTACs possesses particularly concentrated on applications to cancer treatment..."

Clinical • Journal • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma. (PubMed, Leukemia) - "Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL."

IO biomarker • Journal • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Targeted Protein Degradation

[VIRTUAL] A Synthetic Lethal Approach to Eradicate AML Via Synergistic Activation of Pro-Apoptotic p53 By MDM2 and BET Inhibitors (ASH 2020) - "Furthermore, we used BET PROTACs to selectively and completely induce degradation of BRD4 in cells...Taken together, our data show BRD4 represses p53-mediated transcription activation and apoptosis in AML. Therefore, co-targeting wild-type TP53 and a transcriptional repressor function of BRD4 represent a novel synthetic lethal vulnerability in AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • MDM2