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Development of Novel Anticancer Agents with a Scaffold of Tetrahydropyrido[4,3-d]pyrimidine-2,4-dione.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-01-16 , DOI: 10.1021/acsmedchemlett.8b00531 Zonghui Ma 1 , Ge Gao 1 , Kunsen Fang 1 , Haiying Sun 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-01-16 , DOI: 10.1021/acsmedchemlett.8b00531 Zonghui Ma 1 , Ge Gao 1 , Kunsen Fang 1 , Haiying Sun 1
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ONC201 is a small molecular anticancer agent currently in multiple Phase II clinical trials. Based on the pharmacophore of ONC201, a series of small molecular compounds with a core structure of tetrahydropyrido[4,3-d]pyrimidine-2,4-dione were designed and synthesized. Preliminary mechanism studies of these compounds indicated that they can inhibit the phosphorylation of AKT and ERK, induce the dephosphorylation of Foxo3a, and promote the expression of TRAIL and the enhancement of activating transcription factor 4 (ATF4) in PC-3 cells. Structure-activity relationship (SAR) studies indicated that modifications of the substituted groups on the core structure can significantly improve the cellular activities of these compounds. The most potent compounds are over 100 times more potent than ONC201 in inhibition of cell growth in a panel of different types of human cancer cell lines.
中文翻译：
四氢吡啶并[4,3-d]嘧啶-2,4-二酮骨架的新型抗癌药的开发。
ONC201是一种小分子抗癌药，目前正在多项II期临床试验中。基于ONC201的药效团，设计合成了一系列具有四氢吡啶并[4,3-d]嘧啶-2,4-二酮核心结构的小分子化合物。这些化合物的初步机理研究表明，它们可以抑制PC-3细胞中AKT和ERK的磷酸化，诱导Foxo3a的去磷酸化，并促进TRAIL的表达和激活转录因子4（ATF4）的表达。结构-活性关系（SAR）研究表明，核心结构上取代基的修饰可以显着改善这些化合物的细胞活性。
更新日期：2019-01-16
中文翻译：
四氢吡啶并[4,3-d]嘧啶-2,4-二酮骨架的新型抗癌药的开发。
ONC201是一种小分子抗癌药，目前正在多项II期临床试验中。基于ONC201的药效团，设计合成了一系列具有四氢吡啶并[4,3-d]嘧啶-2,4-二酮核心结构的小分子化合物。这些化合物的初步机理研究表明，它们可以抑制PC-3细胞中AKT和ERK的磷酸化，诱导Foxo3a的去磷酸化，并促进TRAIL的表达和激活转录因子4（ATF4）的表达。结构-活性关系（SAR）研究表明，核心结构上取代基的修饰可以显着改善这些化合物的细胞活性。
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