BCL6 degrader | BI-3802
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Highlights
B-cell lymphoma 6 (BCL6) is a known oncogenic driver and frequently overexpressed in many Diffuse large B-cell lymphoma (DLBCL). BI-3802 potently inhibits the interaction of the BTB/POZ domain of BCL6 with several co-repressors in vitro (IC50 ≤ 3 nM). In a cellular context, BI-3802 inhibits the BCL6::Co-repressor complex formation with an IC50 of 43 nM. Moreover, BI-3802 was found to be a potent and efficacious degrader of the BCL6 protein in many DLBCL cell lines (DC50 = 20 nM in SU-DHL-4 cells)1. The good permeability properties of BI-3802 and the so far unprecedented BCL6 degradation effects make this molecule an ideal in vitro probe compound for testing hypotheses around BCL6 biology. With BI-5273 we also offer a structurally close analog which can be used as a negative control for in vitro experiments (IC50 ~ 10 µM)1.
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Target information
B-cell lymphoma 6 (BCL6) functions as a transcriptional repressor that binds specific DNA sequences via its Zn-fingers and recruits transcriptional co-repressors (e.g. BCOR, SMRT, NCOR) by its BTB/POZ domain2. BCL6 is essential for the germinal center (GC) reaction3. It represses a broad set of genes that are required to sustain mutagenic activity without activating the DNA damage response or apoptosis4. BCL6 also prevents maturation to plasma or memory cells and helps to maintain a de-differentiated state. Its expression must be switched off to allow the B-cell to exit the GC cycle and differentiate. BCL6 is a known oncogenic driver of DLBCL5,6 and frequently overexpressed in DLBCL.
BCL6-BTB dimer with BI-3802, as observed by X-ray.1
BI-3802 binds at the interface of two monomers (monomers are shown in green and grey).
In vitro Activity
BI-3802 displays an IC50 ≤ 3 nM in a BCL6::BCOR ULight TR-FRET assay and degrades BCL6 protein with a DC50 of 20 nM (in SU-DHL-4 cell lines)1.
In vitro activity table
|
Probe name / Negative control |
BI-3802 |
BI-5273 |
|
MW [Da] |
485 |
500 |
|
BCL6::BCOR ULight TR-FRET (IC50) [nM]a |
≤ 3 |
10162 |
|
BCL6::NCOR LUMIER (IC50) [nM] |
43 |
n.d. |
|
BCL6 protein degradation (DC50) [nM]b |
20 |
Inactive |
a With affinities of approximately 3 nM, the assay wall of this assay is reached, limiting the accuracy of the biochemical assay.
b in SU-DHL-4 cells
It is recommended to store and use 1 mM DMSO stock solutions of BI-3802 for all in vitro experiments.
In vitro DMPK parameters
In vitro DMPK parameters table
|
Probe name / Negative control |
BI-3802 |
BI-5273 |
|
Solubility @ pH 6.8 [µg/ml] |
< 1 |
84 |
|
CACO permeability @ pH 7.4 [*10-6 cm/s] |
8.5 |
22 |
|
CACO efflux ratio |
0.4 |
0.6 |
|
Human hepatocyte clearance [% QH] |
56 |
n.d. |
|
Plasma protein binding human [%] |
99.95 |
n.d. |
In vivo DMPK parameters
BI-3802 showed poor bioavailability after p.o. administration in mice (see table).
PK profile of BI-3802 after p.o. dosing in mice
|
Pobe name |
BI-3802 |
|
|
Dose [mg/kg] |
10 |
100 |
|
AUD [nMh] |
1860 |
4650 |
|
Cmax [nM] |
193 |
599 |
Negative control
BI-5273 is a close analog of BI-3802 which binds only very weakly to the BCL6 BTB domain (IC50 ~ 10 µM) and does not induce protein degradation.
BI-5273, negative control
Selectivity
Co-crystal structure of the BI probe compound and the target protein
The Xray crystal structure of BCL6 in complex with BI-3802 is available (PDB code: 5MW2).1
reference molecules
Several small molecule BCL6 inhibitors have been published recently7,8,9,10. None of those is described as a BCL6 protein degrader.
Summary
BI-3802 is a single digit nanomolar BCL6::Co-repressor inhibitor which induces efficacious BCL6 protein degradation in several Diffuse large B-cell lymphoma (DLBCL) cell lines (e.g., DC50 = 20 nM in SU-DHL-4 cells).
Supplementary data
References
Chemically induced degradation of the oncogenic transcription factor BCL6
N. Kerres et al.
Cell Rep. 2017, 20(12), 2860-2875.
The BTB domain, found primarily in zinc finger proteins, defines an evolutionarily conserved family that includes several developmentally regulated genes in Drosophila
S. Zollman et al.
Proc. Natl. Acad. Sci. U S A 1994, 91, 10717-10721.
Control of inflammation, cytokine expression, and germinal center formation by BCL-6
A.L. Dent et al.
Science 1997, 276, 589-592.
Integrated biochemical and computational approach identifies BCL6 direct target genes controlling multiple pathways in normal germinal center B cells
K. Basso et al.
Blood 2010, 115, 975-984.
Roles of BCL6 in normal and transformed germinal center B cells
K. Basso and R. Dalla-Favera
Immunol. Rev. 2012, 247, 172-183.
Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis
K. Hatzi and A. Melnick,
Trends Mol. Med. 2014, 20, 343-352.
Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma
M. G. Cardenas et al.
J. Clin. Invest. 2016, 126, 3351-3362.
Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors
W. McCoull et al.
J. Med. Chem. 2017, 60, 4386-4402.
Discovery of a B-cell lymphoma 6 Protein–Protein Interaction Inhibitor by a Biophysics-driven Fragment-based Approach
Y. Kamada et al.
J. Med. Chem. 2017, 60, 4358-4368.
Discovery of a novel B-cell lymphoma 6 (BCL6)-corepressor interaction inhibitor by utilizing structure-based drug design
T. Yasui et al.
Bioorg. Med. Chem. 2017, 25, 4876-4886.
