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设计针对间变性淋巴瘤激酶（ALK）和溴结构域蛋白 4（BRD4）的双重抑制剂：调节激酶选择性。

Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity.

机构信息

Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research , London SM2 5NG , U.K.

Institute for Pharmaceutical Chemistry , Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9 , D-60438 Frankfurt am Main , Germany.

出版信息

J Med Chem. 2019 Mar 14;62(5):2618-2637. doi: 10.1021/acs.jmedchem.8b01947. Epub 2019 Feb 21.

DOI:10.1021/acs.jmedchem.8b01947
PMID:30789735
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6421522/
Abstract

Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1-BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK-BRD4 profile. These efforts led to compound ( R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-methylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5 H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity.

摘要

联合抑制间变性淋巴瘤激酶 (ALK) 和溴结构域蛋白 4 (BRD4) 是一种潜在的治疗策略，可靶向两种关键的致癌驱动因子，这些驱动因子在很大一部分高风险神经母细胞瘤患者中共同分离，即 ALK 突变和 MYCN 扩增。我们从已知的双重 Polo 样激酶 (PLK)-1-BRD4 抑制剂 BI-2536 出发，采用基于结构的设计方法重新设计该系列化合物，以获得具有双重 ALK-BRD4 特征的化合物。这些努力导致化合物 (R)-2-((2-乙氧基-4-(1-甲基哌啶-4-基)苯基)氨基)-7-乙基-5-甲基-8-((4-甲基噻吩-2-基)甲基)-7,8-二氢蝶啶-6(5H)-酮 (16k) 的 ALK 活性得到改善，PLK-1 活性显著降低，同时保持 BRD4 活性和整体激酶组选择性。我们证明了这些化合物在细胞中与 ALK 和 BRD4 的靶标结合，以及对广泛的激酶和溴结构域的良好选择性。

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