Discovery of 5-imidazole-3-methylbenz[d]isoxazole Derivatives As Potent and Selective CBP/p300 Bromodomain Inhibitors for the Treatment of Acute Myeloid Leukemia

Overview

Journal Acta Pharmacol Sin

Date 2025 Jan 31

PMID 39890943

Authors

Jian-Kang Hu

Xin Tang

Guo-Long Luo

Cheng Zhang

Tian-Bang Wu

Chao Wang

Hui Shen

Xiao-Fan Zhao

Xi-Shan Wu

Jeff B Smaill

Yong Xu

Yan Zhang

Qiu-Ping Xiang

Affiliations

Soon will be listed here.

Abstract

Inhibition of the bromodomain of the cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 is an attractive therapeutic approach in oncology, particularly in acute myeloid leukemia (AML). In this study we describe the design, optimization, and evaluation of 5-imidazole-3-methylbenz[d]isoxazoles as novel, potent and selective CBP/p300 bromodomain inhibitors. Two of the representative compounds, 16t (Y16524) and 16u (Y16526), bound to the p300 bromodomain with IC values of 0.01 and 0.03 μM, respectively. Furthermore, 16t and 16u potently inhibited the growth of AML cell lines, particularly MV4;11 cells with IC values of 0.49 and 0.26 μM, respectively. The potent CBP/p300 bromodomain inhibitors represent a new class of compounds for the development of potential therapeutics against AML.

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