Synthesis of diverse lactam carhoxamides leading to the discovery of a new transcription-factor inhibitor
Synthesis of diverse lactam carhoxamides leading to the discovery of a new transcription-factor inhibitor
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DOI：
10.1002/anie.200700762
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Shaw, Jared T.
中科院分区：
文献类型：
--
作者：
Ng, Pui Yee;Tang, Yuchen;Shaw, Jared T.
蛋白质-生物聚合物与小分子相互作用的选择性诱导或破坏对于细胞和疾病生物学的基本分子途径的化学控制是重要的。[1，2]然而，选择性破坏蛋白质-蛋白质和蛋白质-DNA相互作用的化合物的结构要求在很大程度上是未知的。[3]发现蛋白质-生物聚合物相互作用的选择性调节剂的挑战在于合成具有足够复杂性的化合物以与靶蛋白上的适当界面位点相互作用。为了应对这一挑战，我们正在开发新的策略，用于高效合成复杂的小分子文库，用于高通量筛选实验时，活性的结构要求是未知的。[4]在此，我们描述了如何合成和筛选内酰胺甲酰胺库，揭示HOXA 13的新抑制剂，HOXA 13是一种调节哺乳动物发育[5]和某些类型癌症的转录因子。[6]美国
The selective induction or disruption of protein–biopolymer interactions with small molecules is important for the chemical control of molecular pathways fundamental to cell and disease biology.[1, 2] However, the structural requirements for compounds that selectively disrupt protein–protein and protein–DNA interactions are largely unknown.[3] The challenge of discovering selective modulators of protein–biopolymer interactions rests on the synthesis of compounds with sufficient complexity to interact with an appropriate interface site on a target protein. To address this challenge, we are developing new strategies for the efficient synthesis of complex libraries of small molecules for use in high-throughput screening experiments when the structural requirements for activity are not previously known.[4] Herein we describe how the synthesis and screening of a library of lactam carboxamides revealed a new inhibitor of HOXA13, a transcription factor that regulates mammalian development [5] and certain kinds of cancer.[6]