Abstract: Diffuse large B-cell lymphomas (DLBCLs) are life-threatening cancers that are the most common form of non-Hodgkin’s lymphomas. The current standard treatment of DLBCL involves the RCHOP regimen. However many patients treated with those therapies relapse. The transcriptional repressor BCL6 is the most frequently translocated locus in DLBCL. Recent work has shown that BCL6 inhibitors are highly active in BCL6-dependent DLBCL cell lines and primary human DLBCL tumor. The goal of this work is to develop novel therapeutics for DLBCL by selectively inhibiting the oncogenic function of BCL6. Using a series of complementary approaches, including computational chemistry, medicinal chemistry, X-ray crystallography, and cancer biology, we will develop potent and highly specific BCL6 inhibitors, for which we understand their mode of killing, their in vivo efficacy, toxicity and PK, and their activity against primary DLBCL response. Given how powerful and yet non-toxic BCL6 targeted therapy appears to be, BCL6 inhibitors could also serve as an anchor for combination therapies without fear of significant cross-toxicities. Ultimately, we will develop the first clinically tractable inhibitors of a novel therapeutic target, BCL6, as a revolutionary treatment for DLBCL.