Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Feb 16

PMID 36793435

Authors

Ahmed Mamai

Anh M Chau

Brian J Wilson

Iain D Watson

Babu B Joseph

Pandiaraju R Subramanian

Monzur M Morshed

Justin A Morin

Michael A Prakesch

Tianbao Lu

Pete Connolly

Douglas A Kuntz

Neil C Pomroy

Gennady Poda

Kong Nguyen

Richard Marcellus

Graig Strathdee

Brigitte Theriault

Ratheesh Subramaniam

Mohammed Mohammed

Ayome Abibi

Manuel Chan

Jeffrey Winston

Taira Kiyota

Elijus Undzys

Ahmed Aman

Nigel Austin

Marc Du Jardin

Kathryn Packman

Ulrike Phillippar

Riccardo Attar

James Edwards

Jeff OMeara

David E Uehling

Rima Al-Awar

Gilbert G Prive

Methvin B Isaac

Affiliations

Soon will be listed here.

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 (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.

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