Article
Author: Isaac, Methvin B. ; Phillippar, Ulrike ; Lu, Tianbao ; Packman, Kathryn ; Mamai, Ahmed ; Chau, Anh M. ; Privé, Gilbert G. ; Morshed, Monzur M. ; Kiyota, Taira ; Undzys, Elijus ; Kuntz, Douglas A. ; Uehling, David E. ; Connolly, Pete ; Strathdee, Graig ; Aman, Ahmed ; Al-awar, Rima ; Subramanian, Pandiaraju R. ; Abibi, Ayome ; Attar, Riccardo ; Chan, Manuel ; Poda, Gennady ; Edwards, James ; O’Meara, Jeff ; Winston, Jeffrey ; Austin, Nigel ; Prakesch, Michael A. ; Du Jardin, Marc ; Subramaniam, Ratheesh ; Mohammed, Mohammed ; Nguyen, Kong ; Marcellus, Richard ; Morin, Justin A. ; Wilson, Brian J. ; Pomroy, Neil C. ; Theriault, Brigitte ; Joseph, Babu B. ; Watson, Iain D.
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 58 (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies.