期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 11, 期 10, 页码 1993-2001出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.0c00022
关键词
PAINS; Ras; macrocyclic peptides; screening
资金
- A*STAR [H17/01/a0/010, IAF111213C, H18/01/a0/015]
- MSD
Nonspecific promiscuous compounds can mislead researchers and waste significant resources. This phenomenon, though well-documented for small molecules, has not been widely explored for the peptide modality. Here we demonstrate that two purported peptide-based KRas inhibitors, SAH-SOS1(A) and cyclo-rasin 9A5, exemplify false-positive molecules-in terms of both their binding affinities and cellular activities. Through multiple gold-standard biophysical techniques, we unambiguously show that both peptides lack specific binding to KRas and instead induce protein unfolding. Although these peptides inhibited cellular proliferation, the activities appeared to be off-target on the basis of a counterscreen with KRas-independent cell lines. We further demonstrate that their cellular activities are derived from membrane disruption. Accordingly, we propose that to de-risk false-positive molecules, orthogonal binding assays and cellular counterscreens are indispensable.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据