Evaluation of Quinazoline Analogues as Glucocerebrosidase Inhibitors with Chaperone Activity
Evaluation of Quinazoline Analogues as Glucocerebrosidase Inhibitors with Chaperone Activity
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DOI：
10.1021/jm1008902
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发表时间：
2011-02-24
影响因子：
7.3
通讯作者：
Austin, Christopher P.
中科院分区：
文献类型：
--
作者：
Marugan, Juan J.;Zheng, Wei;Austin, Christopher P.
戈谢病是一种由葡萄糖脑苷酶（GC）缺乏引起的溶酶体贮积障碍（LSD）。蛋白质折叠和易位的小分子伴侣被认为是治疗这种LSD的一种有前途的方法。文献中描述的大多数小分子伴侣都含有亚糖支架。在这里，我们提出了发现和评价了一系列新的以喹唑啉为核心的GC抑制剂。我们证明，该系列可以改善患者来源细胞中GC向溶酶体的易位。为了优化该化学系列，进行了系统的合成修饰，并使用三种不同的化合物活性数据（酶抑制、酶热稳定和GC的溶酶体易位）来评估和比较SAR。
Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.