RESUMEN
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.
RESUMEN
Long residence time enzyme inhibitors with a two-step binding mechanism are characterized by a high internal energy barrier for target association. This raises the question of whether optimizing residence time via further increasing this internal energy barrier would inevitably lead to insufficient target occupancy in vivo due to slow, time-dependent binding. We attempted to address this question during optimization of cyclooxygenase-2 (COX-2) inhibitors. Defining long residence time drugs with acceptable association and dissociation rate constants required for sufficient target occupancy and sustained efficacy, which we termed "balanced internal energetics", provides an important criterion for successful progression during lead optimization. Despite the advancement of several COX-2 inhibitors to marketed drugs, their detailed inhibition kinetics have been surprisingly limiting especially during the structure-activity relationship process mainly due to the lack of robust kinetic assays. Herein, we describe a reoptimized COX enzymatic assay and a novel MS-based assay enabling detailed mechanistic studies for identifying long residence time COX-2 inhibitors with balanced internal energetics. These efforts led to the discovery of promising leads possessing dissociation half-lives of ≤40 h, much greater than the values of 6 and 0.71 h for two marketed drugs, etoricoxib and celecoxib, respectively. Importantly, the inhibition rate constants remain comparable to those of the marketed drugs and above the lower limits set by the criteria of balanced internal energetics, predicting sufficient target occupancy required for efficacy. Taken together, this study demonstrates the feasibility of increasing the internal energy barrier as a viable approach for lead optimization toward discovering long residence time drug candidates.
