biostudies-literatureUnknown14(2)Mamai AOntario Institute for Cancer ResearchJohnson and Johnson Research and Development teamMinistry of Research and InnovationB cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein-protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate <b>58</b> (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and ACS medicinal chemistry letters199-210https://www.ebi.ac.uk/biostudies/studies/S-EPMC9923840biostudies-literatureDiscovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor.PMC9923840Watson IDAman AConnolly PMarcellus RKiyota TDu Jardin MAl-Awar RUndzys EPoda GMohammed MPomroy NCPhillippar UAttar RUehling DEAbibi APrakesch MATheriault BWilson BJJoseph BBO'Meara JSubramaniam RChan MSubramanian PREdwards JNguyen KPackman KIsaac MBMamai AMorin JAKuntz DAStrathdee GPrive GGChau AMMorshed MMWinston JLu TAustin NfalseDiscovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor.B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein-protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate <b>58</b> (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and 2023-01-01T00:00:00Z2023 Feb2025-04-19T22:30:02.675Z2025-04-19T22:30:02.675ZS-EPMC99238403679343510.1021/acsmedchemlett.2c00502