气候变化领域集成服务门户(CCPortal): Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential

CCPortal

DOI	10.1073/pnas.2007328118
	Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential
	Wu K.; Huynh K.Q.; Lu I.; Moustakim M.; Miao H.; Yu C.; Haeusgen M.J.; Hopkins B.D.; Huang L.; Zheng N.; Sanchez R.; DeVita R.J.; Pan Z.-Q.
发表日期	2021
ISSN	00278424
卷号	118 期号:8
英文摘要	Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4’s core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4’s substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds’ cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4–expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cullin4; E3 CRL4; Protein degradation; Small-molecule inhibitors; Tumor inhibition
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180532
作者单位	Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, United States; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, United States; Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, United States; HHMI, University of Washington, Seattle, WA 98195-7280, United States; Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, United States; Department of Physiology, University of California, Irvine, CA 92697, United States; Department of Biophysics, University of California, Irvine, CA 92697, United States; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, United States
推荐引用方式 GB/T 7714	Wu K.,Huynh K.Q.,Lu I.,et al. Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential[J],2021,118(8).
APA	Wu K..,Huynh K.Q..,Lu I..,Moustakim M..,Miao H..,...&Pan Z.-Q..(2021).Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential.Proceedings of the National Academy of Sciences of the United States of America,118(8).
MLA	Wu K.,et al."Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential".Proceedings of the National Academy of Sciences of the United States of America 118.8(2021).