ARCC-29 / Arvinas - LARVOL DELTA

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

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

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

Controlled Delivery of BET-PROTACs: In Vitro Evaluation of MZ1-Loaded Polymeric Antibody Conjugated Nanoparticles in Breast Cancer. (PubMed, Pharmaceutics) - "The encapsulation and controlled release of BET-PROTACs through their vectorization with antibodies, like trastuzumab, could facilitate their pharmacokinetic and efficacy profile...Morphology of the nanoparticles, along with stability and release studies, completed the characterization. MZ1-loaded ACNPs showed a significant cytotoxic effect maintaining its mechanism of action and improving its therapeutic properties."

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

PROTAC induced-BET protein degradation exhibits potent anti-osteosarcoma activity by triggering apoptosis. (PubMed, Cell Death Dis) - "Compared with BET inhibitors HJB-97 and JQ1, the activity of BETd-260 increased over 1000 times. Of note, BETd-260 induced degradation of BET proteins, triggered apoptosis in xenograft osteosarcoma tumor tissue, and profoundly inhibited the growth of cell-derived and patient-derived osteosarcoma xenografts in mice. Our findings indicate that BET PROTACs represent a promising therapeutic agent for human osteosarcoma."

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

Proteolysis-targeting chimaeras mediated the degradation of bromodomain and extra-terminal domain proteins. (PubMed, Future Med Chem) - "By using this technology, the heterobifunctional small-molecule BET degraders can induce BET protein degradation. In this review, we discuss the advances in the drug discovery and development of BET-targeting proteolysis-targeting chimaeras."

Journal • Oncology • Targeted Protein Degradation

Multiple myeloma: Combination therapy of BET proteolysis targeting chimeric molecule with CDK9 inhibitor. (PubMed, PLoS One) - "The combination also resulted in marked increase of apoptotic cells at low dose compared to single agent alone. Taken together, our studies show for the first time that the combination of a BET PROTAC (ARV 825) plus AZD 4573 (CDK9 inhibitor) is effective against MM cells."

Combination therapy • Journal • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation

Acquired Resistance to BET-PROTACs(Proteolysis Targeting Chimeras) Caused by Genomic Alterations in Core Components of E3 ligase Complexes. (PubMed, Mol Cancer Ther) - "However, unlike what was often observed for many targeted therapeutics, resistance to BET-PROTACs did not result from secondary mutations that affect compound binding to the target. In contrast, acquired resistance to both VHL- and CRBN-based BET-PROTACs was primarily caused by genomic alterations that compromise core components of the relevant E3 ligase complexes."

Journal • Oncology • Targeted Protein Degradation

Activity of BET-proteolysis targeting chimeric (PROTAC) compounds in triple negative breast cancer. (PubMed, J Exp Clin Cancer Res) - "Using both in vitro and in vivo approaches, we describe the profound activity of BET-PROTACs in parental and BETi-resistant TNBC models. This data provides options for further clinical development of these agents in TNBC."

Journal

Targeting BET Proteins With a PROTAC Molecule Elicits Potent Anticancer Activity in HCC Cells. (PubMed, Front Oncol) - "However, the biological activity of BET-PROTACs in hepatocellular carcinoma (HCC) remains unclear...BETd-260 triggered apoptosis in HCC xenograft tissue and profoundly inhibited the growth of HCC xenograft tumors in mice. Our data suggest that pharmacological targeting of BET for degradation may be a novel therapeutic strategy for the treatment of HCC."

IO Biomarker • Journal • BCL2 • MYC