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

被引：2

作者：

Oh, Danielle H. ^{[3
,4
,5
]}

Ma, Xiao ^{[1
,6
]}

Hogg, Simon J. ^{[2
,5
]}

He, Jackson ^{[3
,6
]}

Kearney, Conor ^{[7
,8
]}

Brasacchio, Daniella ^{[3
]}

Susanto, Olivia ^{[3
]}

Maher, Belinda ^{[3
]}

Jennings, Ian G. ^{[6
]}

Newbold, Andrea ^{[5
,9
]}

Fraser, Peter ^{[5
,9
]}

Gruber, Emily ^{[5
,9
]}

Kats, Lev M. ^{[5
,9
]}

Gregory, Gareth P. ^{[3
,4
,5
]}

Johnstone, Ricky W. ^{[5
,9
]}

Thompson, Philip E. ^{[6
]}

Shortt, Jake ^{[3
,4
,5
,9
]}

机构：

[1] Harvard Med Sch, Dept Syst Biol, Lab Syst Pharmacol, Boston, MA 02115 USA

[2] AbbVie, Oncol Discovery Res, South San Francisco, CA 94080 USA

[3] Monash Univ, Sch Clin Sci, Fac Med Nursing & Hlth Sci, Blood Canc Therapeut Lab,Monash Hlth, Melbourne, Vic 3168, Australia

[4] Monash Hlth, Monash Haematol, Melbourne, Vic 3168, Australia

[5] Peter MacCallum Canc Ctr, Canc Biol Therapeut Program, Melbourne, Vic 3000, Australia

[6] Monash Univ, Monash Inst Pharmaceut Sci, Fac Pharm & Pharmaceut Sci, Med Chem, Parkville, Vic 3052, Australia

[7] Olivia Newton John Canc Res Inst, Heidelberg, Vic 3084, Australia

[8] La Trobe Univ, Sch Canc Med, Heidelberg, Vic 3084, Australia

[9] Univ Melbourne, Sir Peter MacCallum Dept Med Oncol, Melbourne, Vic 3000, Australia

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 36期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

cMYC; phosphatidylinositol-3-kinase; BET-bromodomains; chimeric small molecules; B-CELL LYMPHOMA; DRUG DISCOVERY; BET; APOPTOSIS; CANCER; IDENTIFICATION; EXPRESSION; RESISTANCE; PROTEINS; POTENT;

D O I：

10.1073/pnas.2306414120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 E mu-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.

引用

页数：9

共 20 条

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Slavish, P. Jake
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NEURO-ONCOLOGY, 2015, 17 : 22 - 22
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Pan Gou
Chencheng Fang
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Lu Gan
Jinjin Luo
Hongjuan Cui
Ping Liang
Cell Death Discovery, 11 (1)

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