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Cell-Based Drug Discovery: Identification and Optimization of Small Molecules that Reduce c-MYC Protein Levels in Cells
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2021-10-20 , DOI: 10.1021/acs.jmedchem.1c01416
Jesús R Medina 1 , Xinrong Tian 1 , William H Li 1 , Dominic Suarez 1 , James F Mack 1 , Louis LaFrance 1 , Cuthbert Martyr 1 , James Brackley 1 , Christina Di Marco 1 , Ralph Rivero 1 , Dirk A Heerding 1 , Charles McHugh 2 , Elisabeth Minthorn 2 , Aishwarya Bhaskar 2 , Jacob Rubin 2 , Michael Butticello 2 , Christopher Carpenter 2 , Eldridge N Nartey 1 , Thomas J Berrodin 2 , Lorena A Kallal 1 , Biju Mangatt 2
Affiliation  

Elevated expression of the c-MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small molecule binding pocket in the protein, which could be exploited to disrupt MYC function. We have recently described a strategy to target MYC indirectly, where a screening effort designed to identify compounds that can rapidly decrease endogenous c-MYC protein levels in a MYC-amplified cell line led to the discovery of a compound series that phenocopies c-MYC knockdown by siRNA. Herein, we describe our medicinal chemistry program that led to the discovery of potent, orally bioavailable c-MYC-reducing compounds. The development of a minimum pharmacophore model based on empirical structure activity relationship as well as the property-based approach used to modulate pharmacokinetics properties will be highlighted.

中文翻译:

基于细胞的药物发现:降低细胞中 c-MYC 蛋白水平的小分子的鉴定和优化

c -MYC癌基因的表达升高是人类癌症中最常见的异常之一。不幸的是,由于蛋白质中缺乏任何已知的小分子结合口袋,鉴定直接靶向 MYC 的药理学抑制剂的努力尚未产生类似药物的分子,这可以用来破坏 MYC 功能。我们最近描述了一种间接靶向 MYC 的策略,其中一项筛选工作旨在鉴定可以快速降低 MYC 扩增细胞系中内源性c -MYC蛋白水平的化合物,从而发现了一个化合物系列-通过 siRNA 敲低 MYC。在这里,我们描述了我们的药物化学计划,该计划导致发现了有效的、口服生物可利用的c -MYC 还原化合物。将重点介绍基于经验结构活性关系的最小药效团模型的开发以及用于调节药代动力学特性的基于特性的方法。
更新日期:2021-11-11
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