Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6.

B-cell lymphoma6 ( BCL6) inhibition is a promising mechanism for treating hematological cancersbut high quality chemical probesare necessary to evaluate its therapeutic potential. Here we report potent BCL6inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6based on mass spectrometry analyses following chemical proteomic pull down. Importantly, a proteolysis-targeting chimera(PROTAC) was also developed and shown to significantly degrade BCL6in a number of diffuse large B-cell lymphoma(DLBCL) cell lines, but neither BCL6inhibition nor degradation selectively induced marked phenotypic response. To investigate, we monitored PROTAC directed BCL6degradation in DLBCL OCI-Ly1 cells by immunofluorescence and discovered a residual BCL6population. Analysis of subcellular fractions also showed incomplete BCL6degradation in all fractions despite having measurable PROTAC concentrations, together providing a rationale for the weak antiproliferative response seen w...