Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases.,Journal of Medicinal Chemistry

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Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-08-11 , DOI: 10.1021/acs.jmedchem.0c00962
Kaikai Lv _{1,

2} , Weicong Chen ₃ , Danqi Chen ₁ , Jie Mou ₄ , Huijie Zhang _{1,

2} , Tiantian Fan _{1,

2} , Yanlian Li ₁ , Danyan Cao ₁ , Xin Wang ₁ , Lin Chen ₁ , Jingkang Shen ₁ , Dongsheng Pei ₃ , Bing Xiong ₁

Affiliation

Cancer exhibits diverse heterogeneity with a complicated molecular basis that usually harbors genetic and epigenetic abnormality, which poses a big challenge for single-target agents. In the current work, we proposed a hybrid strategy by incorporating pharmacophores that bind to the acetylated lysine binding pocket of BET proteins with a typical kinase hinge binder to generate novel polypharmacological inhibitors of BET and kinases. Through elaborating the core structure of 6-(pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-one, we demonstrated that this rational design can produce high potent inhibitors of CDK9 and BET proteins. In this series, compound 40 was identified as the potential lead compound with balanced activities of BRD4 (IC₅₀ = 12.7 nM) and CDK9 (IC₅₀ = 22.4 nM), as well as good antiproliferative activities on a small cancer cell panel. Together, the current study provided a new method for the discovery of bromodomain and kinase dual inhibitors rather than only being discovered by serendipity.

中文翻译：

作为BET和激酶多药抑制剂的6-（嘧啶-2-基氨基）-3,4-二氢喹喔啉-2（1H）-酮的合理设计和评估。

癌症表现出多样的异质性，具有复杂的分子基础，通常具有遗传和表观遗传异常，这对单靶标药物构成了巨大挑战。在当前的工作中，我们提出了一种混合策略，即通过结合具有典型激酶铰链结合剂的BET蛋白的乙酰化赖氨酸结合口袋的药效团，来生成BET和激酶的新型多药理学抑制剂。通过阐述6-（嘧啶-2-基氨基）-3,4-二氢喹喔啉-2（1 H）-one的核心结构，我们证明了这种合理的设计可以产生高效的CDK9和BET蛋白抑制剂。在本系列中，化合物40被确定为具有平衡BRD4活性的潜在先导化合物（IC ₅₀= 12.7 nM）和CDK9（IC ₅₀ = 22.4 nM），以及在小癌细胞板上的良好抗增殖活性。总之，当前的研究提供了一种发现溴结构域和激酶双重抑制剂的新方法，而不仅仅是偶然发现。

更新日期：2020-09-10

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