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

2023-09-05

Oh, Danielle H

Ma, Xiao

Hogg, Simon J

He, Jackson

Kearney, Conor

Brasacchio, Daniella

Susanto, Olivia

Maher, Belinda

Jennings, Ian G

Newbold, Andrea

Fraser, Peter

Gruber, Emily

Kats, Lev M

Gregory, Gareth P

Johnstone, Ricky W

Thompson, Philip E

Shortt, Jake

BET-bromodomains

cMYC

chimeric small molecules

phosphatidylinositol-3-kinase

Journal Article

0000-0001-9804-1449

0000-0002-9842-9045

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0000-0002-3154-5121

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0000-0001-5956-9611

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0000-0002-8900-6876

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#PLACEHOLDER_PARENT_METADATA_VALUE#

0009-0001-6955-4955

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0000-0001-8742-8138

#PLACEHOLDER_PARENT_METADATA_VALUE#

#PLACEHOLDER_PARENT_METADATA_VALUE#

0000-0002-5910-7625

0000-0003-3185-6488

10.1073/pnas.2306414120

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.

link

Proceedings of the National Academy of Sciences of the United States of America 2023-09-05; 120(36)

Proceedings of the National Academy of Sciences of the United States of America

1091-6490