BCL6 is the most commonly involved oncogene in diffuse large B-cell lymphomas (DLBCLs), and constitutive expression of BCL6 in GC B-cells causes DLBCL in mice.  It is also frequently expressed in follicular lymphomas (FLs), and may be required for survival of these tumors as well.  BCL6 binds to the SMRT co-repressor through a unique interaction mediated by the N-terminal BTB/POZ domain of BCL6.  Peptides that mimic the SMRT interface can displace SMRT from BCL6.  We have identified small molecules that bind to the BCL6 BTB domain and displace SMRT its repression complex with BCL6.  These compounds specifically re-activate BCL6 target genes, kill BCL6 dependent DLBCL cells in vitro, suppress already established DLBCL tumors in mice, kill primary DLBCL cells from human patients ex vivo, and are non-toxic in animals.  The design and synthesis, as well as the crystallographic analysis and biological evaluation of the new inhibitors will be detailed.

Targeting B-cell lymphoma 6 (BCL6) for the treatment of diffuse large B-cell lymphomas (DLBCLs)

246th National Meeting (2013)

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