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ACS medicinal chemistry letters
Feb 09, 2023;14 (2): 199-210.

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

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 O'Meara, David E Uehling, Rima Al-Awar, Gilbert G Privé, Methvin B Isaac
Author Information
  1. Ahmed Mamai: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  2. Anh M Chau: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  3. Brian J Wilson: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  4. Iain D Watson: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  5. Babu B Joseph: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  6. Pandiaraju R Subramanian: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  7. Monzur M Morshed: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  8. Justin A Morin: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  9. Michael A Prakesch: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  10. Tianbao Lu: Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania19477, United States. ORCID
  11. Pete Connolly: Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania19477, United States.
  12. Douglas A Kuntz: Princess Margaret Cancer Centre, Toronto, OntarioM5G 2C1, Canada.
  13. Neil C Pomroy: Princess Margaret Cancer Centre, Toronto, OntarioM5G 2C1, Canada.
  14. Gennady Poda: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  15. Kong Nguyen: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  16. Richard Marcellus: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  17. Graig Strathdee: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  18. Brigitte Theriault: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  19. Ratheesh Subramaniam: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  20. Mohammed Mohammed: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  21. Ayome Abibi: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  22. Manuel Chan: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  23. Jeffrey Winston: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  24. Taira Kiyota: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  25. Elijus Undzys: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  26. Ahmed Aman: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada. ORCID
  27. Nigel Austin: Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania19477, United States.
  28. Marc Du Jardin: Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania19477, United States.
  29. Kathryn Packman: Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania19477, United States.
  30. Ulrike Phillippar: Janssen Research & Development, Turnhoutseweg 30, B-2340Beerse, Belgium.
  31. Riccardo Attar: Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania19477, United States.
  32. James Edwards: Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania19477, United States.
  33. Jeff O'Meara: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  34. David E Uehling: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  35. Rima Al-Awar: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada.
  36. Gilbert G Privé: Princess Margaret Cancer Centre, Toronto, OntarioM5G 2C1, Canada.
  37. Methvin B Isaac: Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, Suite 510, Toronto, OntarioM5G 0A3, Canada. ORCID
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 (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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Journal Article
Article has an altmetric score of 9

Word Cloud

Created with Highcharts 10.0.0BCL6DLBCLlymphomahighlycelltranscriptionalbindingpotentinhibitorcandidateinhibitionprofileB6regulatedrepressorderegulatedseveralformsnon-HodgkinNHLnotablydiffuselargeB-cellactivitiesdependentprotein-proteininteractionsco-repressorsfindnewtherapeuticinterventionsaddressingneedspatientsinitiatedprogramidentifyinhibitorsinterfereco-repressorvirtualscreenhitactivityhighmicromolarrangeoptimizedstructure-guidedmethodsresultingnovelseriesoptimizationresultedleadOICR12694/JNJ-65234637lownanomolargrowthexcellentoralpharmacokineticBasedoverallfavorablepreclinicalOICR12694orallybioavailabletestingneoplasmsparticularlycombinationtherapiesDiscoveryOICR12694:NovelPotentSelectiveOrallyBioavailableBTBInhibitor

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