Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor
Ahmed Mamai, Anh Chau, Brian J. Wilson, Iain D. G. Watson, Babu Joseph, Pandiaraju R. Subramanian, Monzur M. Morshed, Justin A. Morin, Michaël Prakesch, Tianbao Lu, Pete Connolly, D.A. Kuntz, Neil C. Pomroy, Gennady Poda, Kong T. Nguyen, Richard Marcellus, Graig Strathdee, Brigitte L. Thériault, Ratheesh Subramaniam, Mohammed Mohammed, Ayome Abibi, Manuel Chan, Jeffrey Winston, Taira Kiyota, Elijus Undzys, Asma M. Aman, Nigel Austin, Marc Du Jardin, Kathryn Packman, Ulrike Phillippar, Riccardo Attar, James P. Edwards, Jeff A. O’Meara, David Uehling, Rima Al‐awar, Gilbert G. Privé, Methvin Isaac
Abstract
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.