Molecular Pharmacology of the System xc- Glutamate/Cystine Antiporter

描述（由申请人提供）：本项目的总体目标是推进xc-谷氨酸/胱氨酸反向转运蛋白（Sxc-）系统的新型抑制剂的发现和开发，特别针对转运蛋白上新发现的变构位点。Sxc-是连接L-胱氨酸（L-Cys 2）的输入与L-谷氨酸（L-Glu）的输出的专性交换剂。Sxc功能在CNS中特别关键，因为它介导谷胱甘肽（GSH）合成和氧化保护所需的重要含硫氨基酸的摄取，同时产生兴奋性神经递质的流出，该兴奋性神经递质因其对快速和缓慢突触信号传导、突触可塑性和兴奋性毒性病理的贡献而众所周知。新出现的证据还表明，SxC活性的变化与各种CNS疾病的潜在病理机制相关，其中最突出的是神经胶质脑肿瘤和药物成瘾/复发。不幸的是，我们对Sxc-在中枢神经系统中的功能意义的日益认识已经迅速超过了调节转运蛋白活性的有效和选择性小分子的可用性。我们组最近的合成和SAR为基础的药理学研究已经确定了一个新的系列的有效的非竞争性抑制剂Sxc-我们假设是相互作用的至少两个不同的亲脂性结构域相邻的底物结合位点的转运。我们的鉴定 这类新的非竞争性抑制剂以及因此的先前未被认识的可以变构调节转运蛋白活性的结合位点为抑制剂开发提供了全新的机会。使用合成和药理学评估的迭代循环，通过药效团建模，我们建议建立在我们的先导化合物和优化这些Sxc抑制剂的效力和特异性。提出的合成和药理学研究解决了开发小分子的重大未满足的需求，用小分子来探测Sxc-的功能及其作为治疗靶点的潜力。

DESCRIPTION (provided by applicant): The overall goal of this project is to advance the discovery and development of novel inhibitors of the system xc- glutamate/cystine antiporter (Sxc-), specifically targeting a newly identified allosteric site on the transporter. Sxc- is an obligate exchanger that links the import of L-cystine (L-Cys2) with the export of L-glutamate (L-Glu). Sxc- function is particularly critical in the CNS, as it mediates the uptake of a vital sulfu-containing amino acid needed for glutathione (GSH) synthesis and oxidative protection, while simultaneously producing an efflux of an excitatory neurotransmitter well known for its contributions to fast and slow synaptic signaling, synaptic plasticity and excitotoxic pathology. Emerging evidence also indicates that changes in SxC- activity are associated with the underlying pathological mechanisms of a variety of CNS disorders, the most prominent of which are glial brain tumors and drug addiction/relapse. Unfortunately, our growing appreciation for the functional significance of Sxc- in the CNS has rapidly outpaced the availability of potent and selective small molecules with which to modulate transporter activity. Recent synthetic and SAR-based pharmacological studies in our group have identified a novel series of potent noncompetitive inhibitors of Sxc- that we hypothesize are interacting with at least two distinct lipophilic domains adjacent to the substrate binding site on the transporter. Our identification of this new class of noncompetitive inhibitors and, consequently, a previously unrecognized binding site that can allosterically modulate transporter activity, provides an entirely new opportunity for inhibitor development. Using iterative cycles of synthesis and pharmacological assessment, linked by pharmacophore modeling, we propose to build on our lead compounds and optimize the potency and specificity of these Sxc- inhibitors. The proposed synthetic and pharmacological studies address a significant unmet need in the development of small molecules with which to probe the function of Sxc-, as well as its potential as a therapeutic target.