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The transcription factor B cell lymphoma 6 (BCL6) is required for the generation of an effective humoral immune response through the development and maintenance of germinal centers (GCs). The inhibition of the protein−protein interaction between BCL6 and its corepressors has been implicated as a therapeutic target for diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin’s lymphoma (NHL). Using structure-based drug design, we initiated a program to identify novel BCL6 inhibitors. We identified a high micromolar virtual screening hit which was then optimized for potent biophysical binding and anti-proliferative cellular activity resulting in the identification of OICR-10268, a potent and selective Bcl6 inhibitor. Citation Format: Iain D. Watson, Methvin Isaac, Brian Wilson, Anh Chau, Justin Morin, Pandiaraju Subramanian, Ahmed Mamai, Babu Joseph, Michael Prakesch, David Uehling, Ayome Abibi, Richard Marcellus, Craig Strathdee, Ratheesh Subramaniam, Brigitte Theriault, Jeffrey Winston, Manuel Chan, Carly Griffin, Herman Cheung, Taira Kiyota, Elijus Undzys, Ahmed Aman, Gennady Poda, Doug Kuntz, Neil C. Pomroy, Gil G. Privé, Rima Al-awar. Discovery of OICR-10268: A potent and selective BCL6 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 7.