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Abstract

BCL6 is the most commonly involved oncogene in B cell lymphomas. Depletion or blockade of BCL6 potently kills DLBCL cells and BCL6 is thus a critical therapeutic target. Like many oncogenes and tumors suppressors, BCL6 is a transcription factor. Because such proteins usually mediate their actions through extensive protein interaction surfaces, they have been considered nonamenable to targeting with small molecules. Herein, we used an integrated biochemical and computational approach to identify an effective and specific BCL6 small-molecule inhibitor. This drug displayed favorable pharmacokinetics, pharmacodynamics, toxicity, and therapeutic efficacy. This work demonstrates that oncogenic transcriptional repressors can be therapeutically targeted with small molecules and presents a rationally designed transcription therapy approach for the treatment of lymphomas.