当前位置: X-MOL 学术ACS Med. Chem. Lett. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Chemical Proteomic Characterization of a Covalent KRASG12C Inhibitor
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-05-21 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00110
Aruna Wijeratne 1 , Junpeng Xiao 1 , Christopher Reutter 1 , Kelly W. Furness 1 , Rebecca Leon 1 , Mohammad Zia-Ebrahimi 1 , Rachel N. Cavitt 1 , John M. Strelow 1 , Robert D. Van Horn , Sheng-Bin Peng , David A. Barda 1 , Thomas A. Engler 1 , Michael J. Chalmers 1
Affiliation  

The KRASG12C protein product is an attractive, yet challenging, target for small molecule inhibition. One option for therapeutic intervention is to design small molecule ligands capable of binding to and inactivating KRASG12C via formation of a covalent bond to the sulfhydryl group of cysteine 12. In order to better understand the cellular off-target interactions of Compound 1, a covalent KRASG12C inhibitor, we have completed a series of complementary chemical proteomics experiments in H358 cells. A new thiol reactive probe (TRP) was designed and used to construct a cellular target occupancy assay for KRASG12C. In addition, the thiol reactive probes allowed us to profile potential off-target interactions of Compound 1 with over 3200 cysteine residues. In order to complement the TRP data we designed Compound 2, an alkyne containing version of Compound 1, to serve as bait in competitive chemical proteomics experiments. Herein, we describe and compare data from both the TRP and the click chemistry probe pull down experiments.

中文翻译:

共价KRASG12C抑制剂的化学蛋白质组学表征

KRASG12C蛋白产品是抑制小分子的诱人但具有挑战性的目标。治疗干预的一种选择是设计能够通过与半胱氨酸12的巯基形成共价键而与KRASG12C结合并使其失活的小分子配体。为了更好地理解化合物1的细胞脱靶相互作用,共价KRASG12C抑制剂,我们已经在H358细胞中完成了一系列互补的化学蛋白质组学实验。设计了一种新的硫醇反应探针(TRP),并用于构建KRASG12C的细胞靶标占用分析。此外,硫醇反应性探针使我们能够分析化合物1潜在的脱靶相互作用具有3200多个半胱氨酸残基。为了补充TRP数据,我们设计了化合物2(一种含有炔烃的化合物1)作为诱饵,用于竞争性蛋白质组学实验。在这里,我们描述和比较来自TRP和点击化学探针下拉实验的数据。
更新日期:2018-05-21
down
wechat
bug