BI-3802 / Boehringer Ingelheim - LARVOL DELTA

Non-Coding Mutations of BCL6 in Classical Hodgkin Lymphoma (ASH 2024) - P, P=N/A | "Compared to the BI-5372 control molecule, treatment with BI-3802 significantly decreased proliferation in all cell lines where BCL6 degradation was observed, as well as in the BCL6-dependent SU-DHL4 DLBCL cell line, which was used as a control. Conclusion : This study broadens the understanding of known oncogenic mechanisms in cHL development and identifies BCL6 as a vulnerability in a fraction of cHL and as a potential therapeutic target."

B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Classical Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • BCL6 • BCL7A • CD83 • H1-4 • PAX5 • PRDM1 • SOCS1 • ST6GAL1

NEW UNDERSTANDING OF ONCOGENIC MECHANISMS IN CLASSICAL HODGKIN LYMPHOMA (ISHL 2024) - P, P=N/A | "BCL6 protein degradation was observed with BI-3802 in cell lines expressing BCL6... This study broadens the understanding of known oncogenic mechanisms in cHL development and identifies novel deregulated gene targets (BCL6) relevant to therapy and prognostic biomarkers (WGD)."

Diffuse Large B Cell Lymphoma • Epstein-Barr Virus Infections • Hematological Malignancies • Hodgkin Lymphoma • Infectious Disease • Lymphoma • Oncology • Targeted Protein Degradation • BCL6 • CCNE1 • PRDM1 • STAT6

A platform to induce and mature biomolecular condensates using chemicals and light. (PubMed, Nat Chem Biol) - "Here we used the BCL6 BTB domain and its ligands BI-3802 and BI-3812 to create a chemical genetic platform, BTBolig, allowing inducible condensate formation and dissolution. We also developed optogenetic and chemical methods for controlled induction of condensate maturation, where we surprisingly observed recruitment of chaperones into the condensate core and formation of dynamic biphasic condensates. Our work provides insights into the interaction of condensates with proteostasis pathways and introduces a suite of chemical-genetic approaches to probe the role of biomolecular condensates in health and disease."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • BCL6

Targeting BCL6 in gastrointestinal stromal tumor promotes p53-mediated apoptosis to enhance the antitumor activity of imatinib. (PubMed, Cancer Res) - "Concordantly, treatment of GIST cells showing high BCL6 expression with a BCL6 inhibitor, BI-3802, conferred IM sensitivity. Furthermore, BI-3802 showed striking synergy with IM in IM-responsive and IM-resistant GIST cells in vitro and in vivo. Thus, these findings reveal a role for BCL6 in IM resistance and suggest that a combination of BCL6 inhibitors and IM could be a potentially effective treatment for GIST."

Journal • Stroma • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • BCL6 • SIRT1

Optical tweezers experiments reveal anticancer drug BI-3802 binds DNA in the micromolar range. (PubMed, Biophys J) - No abstract available

Journal • Oncology

Impact of SNPs, off-targets, and passive permeability on efficacy of BCL6 degrading drugs assigned by virtual screening and 3D-QSAR approach. (PubMed, Sci Rep) - "Lifitegrast (DB11611) had favorable binding properties and biological activity compared to the BI-3802. It should also be noted that energetically less desirable passive membrane translocation of Lifitegrast would demand drug delivery vehicles. However, further empirical evaluation of Lifitegrast would unveil its true potential."

Journal • Hematological Malignancies • Lymphoma • Oncology • BCL6

Targeted protein degradation for the treatment of cancer (ACS-Fall 2022) - "Thalidomide analogs, including lenalidomide and pomalidomide, act through targeted protein degradation and are highly effective drugs for the treatment of multiple myeloma, myelodysplastic syndrome (MDS) with del(5q), and some B cell lymphomas. The molecule CR8 acts a molecular glue between DDB1 and CDK12, enabling CDK12 to act as a substrate receptor for an E3 ubiquitin ligase complex, resulting in the targeted degradation of cyclin K. BI-3802 acts as a molecular glue between one BCL6 homodimer and another BCL6 homodimer, resulting in the polymerization and subsequent degradation of BCL6. These studies illustrate the emerging potential of small molecules to act as molecular glues between proteins and to induce targeted protein degradation."

Hematological Malignancies • Lymphoma • Multiple Myeloma • Myelodysplastic Syndrome • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • BCL6 • CDK12 • CRBN • DDB1 • IKZF1 • IKZF3

Bcl6 Regulates NFκB-Controlled Endothelial Inflammation and Apoptosis (ATC 2022) - "* Using pharmacological inhibitors of BCL6 (79-6, FX1, BI-3812, BI-3802) and siRNA in primary human endothelial cells (EC), the impact of BCL6 on TNFα-induced NFκB activity, adhesion molecule and chemokine expression, and global transcriptome changes, was measured with an NFκB-luciferase reporter, flow cytometry, Luminex, and RNA-Seq, and re-analysis of public Molecular Microscope datasets of cardiac allograft rejection, and ENCODE ChIP-Seq data of the BCL6 cistrome. Our results show that BCL6 regulates NFκB-dependent transcription in endothelium, potentially through chromatin remodeling. We conclude that BCL6 is involved in the initiation, magnitude and termination of inflammation and is implicated in the apoptosis response driven by NFκB in cardiac endothelial cells, and may be a therapeutic target to ameliorate vascular inflammation in transplant rejection."

Cardiovascular • Hematological Malignancies • Immunology • Inflammation • Lymphoma • Oncology • Transplant Rejection • Transplantation • BCL6 • CX3CL1 • IL6 • TNFA • VCAM1

BTB dimers as building blocks for reversible drug-induced protein oligomerization. (PubMed, Cell Rep Methods) - "Here, we characterize the BTB domain of the transcription factor BCL6 (BTB) as a small-molecule-controlled, reversible oligomerization switch, which oligomerizes upon BI-3802 treatment and de-oligomerizes upon addition of BI-3812. Finally, BI-3802-induced oligomerization of the EGFR-BTB fusion enhanced proliferation of an EGF-dependent cell line in absence of EGF. These results demonstrate the successful application of small-molecule-induced, reversible oligomerization as a switch for synthetic biology."

Journal • BCL6 • EGFR

"#RESEARCHERS: We are pleased to invite you to attend an #opnMe online seminar on the discovery of BCL6 degrader BI-3802 and the striking findings which helped to understand its unique mode of action" (@Boehringer)

BCL6

BI-3802 Promotes Polymerization and Degradation of Oncogenic BCL6. (PubMed, Cancer Discov) - "The small-molecule drug BI-3802 induced the formation of BCL6 filaments leading to degradation."

Journal • Oncology • BCL6

Small-molecule-induced polymerization triggers degradation of BCL6. (PubMed, Nature) - "The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets, but a substantial subset of proteins are resistant to targeted degradation using existing approaches. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology."

Journal • Hematological Malignancies • Lymphoma • Oncology • Targeted Protein Degradation • BCL6

"2/9 Three years ago, @Boehringer published that BI-3802 degrades BCL6 by an unknown mechanism. How does it work? We fused BCL6 to eGFP and showed that BI-3802 induces efficient proteasome-mediated degradation of the fusion protein." (@biomiko)

BCL6