BI-3812 / Boehringer Ingelheim - LARVOL DELTA

Rewiring Cancer Drivers to Induce Apoptosis By Transcriptional Chemical Inducers of Proximity in Chronic Lymphocytic Leukemia (ASH 2024) - "CDK9-BCL6 TCIPs are designed and produced by covalently linking BI-3812 (binding to BCL6) and SNS-032 (binding to CDK9) with a rigid linker. This study is the first of a kind demonstration of TCIPs in robustly targeting CLL B cells. Further studies to fully validate the preclinical activity of TCIPs and investigate the molecular mechanism(s) for TCIP mediated killing of leukemic B cells will help to define the role of TCIPs as a novel therapeutic approach in CLL."

IO biomarker • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL2 • BCL6 • BRD4 • BTK • CD5 • CDK9 • TP53

Rewiring cancer drivers to induce apoptosis in chronic lymphocytic leukemia (AACR 2025) - "TCIP2 is designed and produced by covalently linking BI-3812 (BCL6 inhibitor) as a BCL6 binder and SNS-032 (CDK9 inhibitor) as a CDK9 binder with a rigid linker. This is the first study of TCIPs ability to target CLL B cells from both untreated and RR patients. Further studies to more fully evaluate the preclinical activity of TCIPs and investigate the molecular mechanism(s) for TCIP mediated killing of leukemic B cells will help to define the potential role of TCIPs as a novel therapeutic approach in CLL."

B Cell Lymphoma • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL6 • BRD4

Pharmaceutical inhibition of BCL6 ameliorates resistance to imatinib in chronic myeloid leukemia. (PubMed, Heliyon) - "CML cells with higher levels of BCL6 were generally sensitive to treatment with BCL6 inhibitors, BI-3812. Treatment of CML cells with BCL6 inhibitor and TKIs suggested enhanced anti-leukemia activity. In summary, our findings suggest BCL6 as a therapeutic target for the treatment of CML."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • BCL6

Rewiring EWS/FLI1 with transcriptional chemical inducers of proximity (TCIPs) (AACR 2024) - "In our proof-of-concept study we used TCIP1 consisting of ortho-AP1867 (oAP), a synthetic ligand for FKBPF36V, linked to the BCL6 inhibitor BI3812 (BI) to rewire N-FK-E/F...Since ES is driven solely by E/F, TCIPs may be promising next generation therapeutics. Our study provides a proof-of-concept that will be the foundation for the development of future TCIP molecules that recruit endogenous E/F once suitable ligands are developed."

Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • BCL6 • BRD4 • CDKN1A • EWSR1 • FLI1

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

Molecular replacement for small-molecule crystal structure determination from X-ray and electron diffraction data with reduced resolution. (PubMed, Acta Crystallogr A Found Adv) - "These data were subsequently used for MR with different data types, varying the data resolution limit (1, 1.5 and 2 Å) and by using search models consisting of connected or disconnected fragments of BI-3812. MR was successful with 3D ED data at 2 Å resolution using a search model that represented 74% of the complete molecule."

Journal • Oncology • BCL6

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