Rationally designed chimeric PI3K-BET bromodomain inhibitors elicit curative responses in MYC-driven lymphoma-Reference-Cited by-同舟云学术

Rationally designed chimeric PI3K-BET bromodomain inhibitors elicit curative responses in MYC-driven lymphoma

Published:2023-08-29 Issue:36 Volume:120 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Oh Danielle H.¹²³^ORCID,Ma Xiao⁴⁵^ORCID,Hogg Simon J.³⁶,He Jackson¹⁴^ORCID,Kearney Conor⁷⁸,Brasacchio Daniella¹^ORCID,Susanto Olivia¹,Maher Belinda¹^ORCID,Jennings Ian G.⁴,Newbold Andrea³⁹,Fraser Peter³⁹^ORCID,Gruber Emily³⁹,Kats Lev M.³⁹^ORCID,Gregory Gareth P.¹²³,Johnstone Ricky W.³⁹,Thompson Philip E.⁴^ORCID,Shortt Jake¹²³⁹^ORCID

Affiliation:

1. Blood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Faculty of Medicine Nursing and Health Sciences, Monash University, Melbourne VIC 3168, Australia

2. Monash Haematology, Monash Health, Melbourne VIC 3168, Australia

3. Cancer Biology Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne VIC 3000, Australia

4. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville VIC 3052, Australia

5. Department of Systems Biology, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115

6. Oncology Discovery Research, Abbvie, South San Francisco, CA 94080

7. Olivia Newton-John Cancer Research Institute, Heidelberg VIC 3084, Australia

8. School of Cancer Medicine, La Trobe University, Heidelberg VIC 3084, Australia

9. Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne VIC 3000, Australia

Abstract

Targeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signaling demonstrate potent but self-limited antilymphoma activity as single agents in the context of cellular Myelocytomatosis ( cMYC ) oncogene-dysregulation. However, combined PI3K and BET inhibition imparts synergistic anticancer activity with the potential for more sustained disease responses due to the mutual antagonism of compensatory epigenetic and signaling networks. Here, we describe the mechanistic and therapeutic validation of rationally designed dual PI3K/BET bromodomain inhibitors, built by linkage of established PI3K and BET inhibitor pharmacophores. The lead candidate demonstrates high selectivity, nanomolar range cellular potency, and compelling in vivo efficacy, including curative responses in the aggressive Eµ- Myc lymphoma model. These studies further support the therapeutic strategy of combined PI3K and BET inhibition and provide a potential step-change in approach to orthogonal MYC antagonism using optimized chimeric small-molecule technology.

Funder

DHAC | National Health and Medical Research Council

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2306414120

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