Chemoproteomics-Enabled Covalent Ligand Screening Reveals ALDH3A1 as a Lung Cancer Therapy Target.
Chemoproteomics-Enabled Covalent Ligand Screening Reveals ALDH3A1 as a Lung Cancer Therapy Target.
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化学蛋白质组学的共价配体筛选显示ALDH3A1是肺癌治疗靶标。
DOI：
10.1021/acschembio.8b00381
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发表时间：
2018-08-17
影响因子：
4
通讯作者：
Nomura DK
中科院分区：
文献类型：
--
作者：
Counihan JL;Wiggenhorn AL;Anderson KE;Nomura DK
化学遗传学是鉴定治疗活性小分子的有力方法，但鉴定靶化合物的作用机制仍然具有挑战性。化学蛋白质组学平台已经出现来应对这一挑战，并使小分子筛选命中的快速机械解卷积成为可能。在这里，我们已经筛选了半胱氨酸反应性共价配体库，以确定命中化合物，损害非小细胞肺癌细胞的细胞存活和增殖，但不是在原代人支气管上皮细胞。通过这次筛选，我们发现了一种共价配体DKM 3 - 42，它会损害原位和体内肺癌的致病性。我们使用基于活性的蛋白质谱发现DKM 3 - 42的主要靶标是醛脱氢酶3A1（ALDH 3A1）中的催化半胱氨酸。我们进行了进一步的化学蛋白质组学直接针对ALDH3A1的共价配体筛选，并确定了更有效和选择性的先导共价配体EN 40，其抑制ALDH3A1活性并削弱肺癌致病性。我们在这里表明，ALDH3A1代表了一个潜在的新的肺癌治疗靶点，表达ALDH3A1，并提出了两个选择性ALDH3A1抑制剂。总的来说，我们展示了将共价配体文库的化学遗传学筛选与化学蛋白质组学方法相结合以快速识别抗癌先导物和靶点的实用性。
Chemical genetics is a powerful approach for identifying therapeutically active small-molecules, but identifying the mechanisms of action underlying hit compounds remains challenging. Chemoproteomic platforms have arisen to tackle this challenge and enable rapid mechanistic deconvolution of small-molecule screening hits. Here, we have screened a cysteine-reactive covalent ligand library to identify hit compounds that impair cell survival and proliferation in non-small cell lung carcinoma cells, but not in primary human bronchial epithelial cells. Through this screen, we identified a covalent ligand hit, DKM 3–42 which impaired both in situ and in vivo lung cancer pathogenicity. We used activity-based protein profiling to discover that the primary target of DKM 3–42 was the catalytic cysteine in aldehyde dehydrogenase 3A1 (ALDH3A1). We performed further chemoproteomics-enabled covalent ligand screening directly against ALDH3A1, and identified a more potent and selective lead covalent ligand, EN40, which inhibits ALDH3A1 activity and impairs lung cancer pathogenicity. We show here that ALDH3A1 represents a potentially novel therapeutic target for lung cancers that express ALDH3A1 and put forth two selective ALDH3A1 inhibitors. Overall, we show the utility of combining chemical genetics screening of covalent ligand libraries with chemoproteomic approaches to rapidly identify anti-cancer leads and targets.
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影响因子：
8.8
作者：
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通讯作者：
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影响因子：
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通讯作者：
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影响因子：
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通讯作者：
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