2. Academic Validation
  3. Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor

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

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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