Targeting apoptosis via chemical design: Inhibition of bid-induced cell death by small organic molecules
Targeting apoptosis via chemical design: Inhibition of bid-induced cell death by small organic molecules
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DOI：
10.1016/j.chembiol.2004.05.022
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发表时间：
2004-08-01
影响因子：
--
通讯作者：
Pellecchia, M
中科院分区：
文献类型：
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作者：
Becattini, B;Sareth, S;Pellecchia, M
Bid是Bcl-2家族蛋白的关键成员，参与细胞凋亡级联反应的控制，导致细胞死亡。不受控制的细胞死亡与几种人类病理学有关，例如神经退行性疾病和缺血性损伤。因此，Bid代表了一个潜在的尚未开发的和具有挑战性的目标，旨在开发治疗药物的战略。在这里，我们表明，一个多学科的NMR为基础的方法，我们命名为SAR的EQUES（结构活性关系的interligand核Overhauser效应），使我们能够合理地设计一系列的4-苯硫基苯胺衍生物，能够占据一个深的疏水裂缝的表面上的出价。这些化合物代表了第一个靶向Bcl-2蛋白的抗凋亡小分子，如通过其抑制tBid诱导的SMAC释放、半胱天冬酶-3活化和细胞死亡的能力所示。
Bid is a key member of the Bcl-2 family proteins involved in the control of the apoptotic cascade in cells, leading to cell death. Uncontrolled cell death is associated with several human pathologies, such as neurodegenerative diseases and ischemic injuries. Therefore, Bid represents a potential yet unexplored and challenging target for strategies aimed at the development of therapeutic agents. Here we show that a multidisciplinary NMR-based approach that we named SAR by ILOEs (structure activity relationships by interligand nuclear Overhauser effect) allowed us to rationally design a series of 4-phenylsulfanyl-phenylamine derivatives that are capable of occupying a deep hydrophobic crevice on the surface of Bid. These compounds represent the first antiapoptotic small molecules targeting a Bcl-2 protein as shown by their ability to inhibit tBid-induced SMAC release, caspase-3 activation, and cell death.