可药性
泛素
胰腺癌
蛋白质组
小分子
计算生物学
药物发现
化学
生物化学
半胱氨酸
共价键
生物
蛋白质水解
癌症
癌症研究
酶
遗传学
有机化学
基因
作者
Allison M. Roberts,David K. Miyamoto,Tucker R. Huffman,Leslie A. Bateman,Ashley N. Ives,David Akopian,Martin J. Heslin,Carlo M. Contreras,Michael Rapé,Christine F. Skibola,Daniel K. Nomura
标识
DOI:10.1021/acschembio.7b00020
摘要
Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy. Through this coupled approach, we have discovered a covalent ligand DKM 2-93 that impairs pancreatic cancer cell survival and in vivo tumor growth through covalently modifying the catalytic cysteine of the ubiquitin-like modifier activating enzyme 5 (UBA5), thereby inhibiting its activity as a protein that activates the ubiquitin-like protein UFM1 to UFMylate proteins. We show that UBA5 is a novel pancreatic cancer therapeutic target and show DKM 2-93 as a relatively selective lead inhibitor of UBA5. Our results underscore the utility of coupling the screening of covalent ligand libraries with isoTOP-ABPP platforms for mining the proteome for druggable hotspots for cancer therapy.
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