Oral BCL6 degrader
Information
Call for collaboration proposals
For a short period of time, we share the unprecedented, potent and selective orally bioavailable BCL6 degrader BI-1136 which is suited for both in vitro and in vivo experiments for collaborative research on novel disease indications. BI-1136 potently degrades human and mouse BCL6 (DC50 = 63 nM in SU-DHL-4 cells). Funding of up to 200.000 € will be available upon request and shall be outlined in the application.
We invite scientists to submit proposals containing an in vivo testable hypothesis using our oral BCL6 degrader no later than July 31, 2019, 23.59 pm PST.
Target information
The transcriptional regulator BCL6 represses genes required for the differentiation of B-cells in germinal centers (GC). Errors in the GC reaction can give rise to mutated B cells that maintain an elevated proliferation and fail to differentiate, contributing to the genesis of Diffuse large B-cell lymphoma (DLBCL). BCL6 is an oncogenic driver for DLBCL (Basso and Dalla-Favera, 2012; Hatzi and Melnick, 2014; Pasqualucci, 2013) and its expression is frequently elevated by mutations in DLBCL. However, despite significant research efforts, the clinical relevance of targeting BCL6 in DLBCL remains to be proven.
In a cellular context, BI-1136 inhibits the BCL6::Co-repressor complex formation with an IC50 of 210 nM. Moreover, BI-1136 was found to be a potent and efficacious degrader of the BCL6 protein in mouse and human DLBCL cell lines (DC50 = 63 nM in SU-DHL-4 cells) as well as in other BCL6 expressing cells tested (macrophages, NSCLC, Burkitt and Breast cancer cell lines). The BCL6 degrader BI-1136 shows pharmacokinetic (PK) properties that are suitable for in vivo testing in several animal species and is well tolerated. A negative control (distomer) having a differentiated pharmacological profile may also be available for sharing on request. The compound will be provided free of charge in the amount required for the experiments, and is provided under an existing collaboration agreement with FORMA Therapeutics, Inc. (Watertown, MA).
In Vitro Activity
BI-1136 potently inhibits the interaction of the BTB/POZ domain of BCL6 with several co-repressors in vitro (IC50 ≤ 50 nM). In a cellular context, the BCL6 degrader inhibits the BCL6::co-repressor complex formation with an IC50 of 210 nM. Moreover, our BCL6 degrader was found to be a potent and efficacious degrader of the BCL6 protein in many human and mouse DLBCL cell lines (SU-DHL-4 DC50 = 63 nM) and induces BCL6 target genes in SU-DHL-4 cells with an EC50 of 60-200nM. Interestingly we found that the BCL-6 degrader BI-1136 displays significantly stronger induction of expression of BCL6-repressed genes than compounds that merely inhibit co-repressor interactions. The BCL6 degrader is mouse cross-reactive and highly selective for BCL6.
|
Assay |
IC50 [nM] |
| BCL6::NCOR1 TR-FRET |
47 |
| BCL6::NCOR1 HEK293 Lumier |
210 |
| BCL6 degradation SU-DHL-4 |
63 |
| RAPGEF1 QPCR SU-DHL-4 |
188 |
In vitro DMPK parameters
BI-1136 has acceptable solubility in water at neutral pH, high permeability in Caco2 and MDCK assays and medium plasma protein binding.
In vivo DMPK parameters
The oral BCL6 degrader BI-1136 differentiates itself from the other BCL6 degrader BI-3802 on opnMe.com in its suitability for in vivo experiments in animals.
PK properties in several animal species are suitable for once or twice daily oral dosing in acute or sub-chronic in vivo experiments, resulting in significant but not complete degradation of BCL6 in SU-DHL-4 xenografts.
Selectivity
BI-1136 shows high selectivity at 10 µM concentration versus a panel of 44 receptors (no inhibition) and 42 Kinases (no inhibition). The compound is well tolerated in mice up to 1g/kg daily dose.
Summary
With BI-1136 we share an unprecedented, potent and selective orally bioavailable BCL6 degrader for collaborative research on novel disease indications. This tool compound potently inhibits the interaction of the BTB/POZ domain of BCL6 with several co-repressors in vitro (IC50 ≤ 50 nM). In a cellular context, the BCL6 degrader inhibits the BCL6::Co-repressor complex formation with an IC50 of 210 nM. Moreover, our BCL6 degrader was found to be a potent and efficacious degrader of the BCL6 protein in mouse and human DLBCL cell lines (DC50 = 63 nM in SU-DHL-4 cells) as well as in other BCL6 expressing cells tested (macrophages, NSCLC, Burkitt and breast cancer cell lines). The BCL6 degrader shows pharmacokinetic (PK) properties that are suitable for in vivo testing in several animal species and is well tolerated. The compound will be provided free of charge in the amount required for the experiments, and is provided under an existing collaboration agreement with FORMA Therapeutics, Inc. (Watertown, MA).
The oral BCL6 degrader BI-1136 differentiates itself from the other BCL6 degrader BI-3802 on opnMe.com in its suitability for in vivo experiments in animals.
We invite scientists to submit proposals containing an in vivo testable hypothesis using our BCL6 degrader no later than July 31, 2019 23.59 pm PST.
References
Roles of BCL6 in normal and transformed germinal center B cells
Basso, K., and Dalla-Favera, R.
Immunol. Rev. 2012, 247, 172–183.
Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis
Hatzi, K., and Melnick, A.
Trends Mol. Med. 2014, 20, 343–352.
Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6
Kerres, N., and Koegl, M.
Cell Reports 2017, 20, 2860–2875.
Inactivating mutations of acetyltransferase genes in B-cell lymphoma
Pasqualucci, L., Dominguez-Sola, D., Chiarenza, A., Fabbri, G., Grunn, A., Trifonov, V., Kasper, L.H., Lerach, S., Tang, H., Ma, J., et al.
Cell Reports 2011, 471, 189–195.