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

  • ACS Med Chem Lett. 2023 Jan 12;14(2):199-210. doi: 10.1021/acsmedchemlett.2c00502.
Ahmed Mamai  1 ,  Anh M Chau  1 ,  Brian J Wilson  1 ,  Iain D Watson  1 ,  Babu B Joseph  1 ,  Pandiaraju R Subramanian  1 ,  Monzur M Morshed  1 ,  Justin A Morin  1 ,  Michael A Prakesch  1 ,  Tianbao Lu  2 ,  Pete Connolly  2 ,  Douglas A Kuntz  3 ,  Neil C Pomroy  3 ,  Gennady Poda  1  4 ,  Kong Nguyen  1 ,  Richard Marcellus  1 ,  Graig Strathdee  1 ,  Brigitte Theriault  1 ,  Ratheesh Subramaniam  1 ,  Mohammed Mohammed  1 ,  Ayome Abibi  1 ,  Manuel Chan  1 ,  Jeffrey Winston  1 ,  Taira Kiyota  1 ,  Elijus Undzys  1 ,  Ahmed Aman  1  4 ,  Nigel Austin  2 ,  Marc Du Jardin  2 ,  Kathryn Packman  2 ,  Ulrike Phillippar  5 ,  Riccardo Attar  2 ,  James Edwards  2 ,  Jeff O'Meara  1 ,  David E Uehling  1 ,  Rima Al-Awar  1  6  7 ,  Gilbert G Privé  3  8  9 ,  Methvin B Isaac  1
Affiliations
  • 1. Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  • 2. Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania19477, United States.
  • 3. Princess Margaret Cancer Centre, Toronto, OntarioM5G 2C1, Canada.
  • 4. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, OntarioM5S 3M2, Canada.
  • 5. Janssen Research & Development, Turnhoutseweg 30, B-2340Beerse, Belgium.
  • 6. Department of Chemistry, University of Toronto, Toronto, OntarioM5S 3H6, Canada.
  • 7. Department of Pharmacology and Toxicology, University of Toronto, Toronto, OntarioM5S 1A8, Canada.
  • 8. Department of Medical Biophysics, University of Toronto, Toronto, OntarioM5G 1L7, Canada.
  • 9. Department of Biochemistry, University of Toronto, Toronto, OntarioM5S 1A8, Canada.
PMID: 36793435 DOI: 10.1021/acsmedchemlett.2c00502
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.

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