title: Ainsliadimer A selectively inhibits IKKα/β by covalently binding a conserved cysteine.
abstract: Aberrant activation of NF-κB is associated with the development of cancer and autoimmune and inflammatory diseases. IKKs are well recognized as key regulators in the NF-κB pathway and therefore represent attractive targets for intervention with small molecule inhibitors. Herein, we report that a complex natural product ainsliadimer A is a potent inhibitor of the NF-κB pathway. Ainsliadimer A selectively binds to the conserved cysteine 46 residue of IKKα/β and suppresses their activities through an allosteric effect, leading to the inhibition of both canonical and non-canonical NF-κB pathways. Remarkably, ainsliadimer A induces cell death of various cancer cells and represses in vivo tumour growth and endotoxin-mediated inflammatory responses. Ainsliadimer A is thus a natural product targeting the cysteine 46 of IKKα/β to block NF-κB signalling. Therefore, it has great potential for use in the development of anticancer and anti-inflammatory therapies.
authors: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.|National Institute of Biological Sciences (NIBS), Beijing 102206, China.
authors: Ting
authors: T
authors: Dong
authors: Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors: Chao
authors: C
authors: Li
authors: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China.
authors: Xing
authors: X
authors: Wang
authors: National Institute of Biological Sciences (NIBS), Beijing 102206, China.
authors: Longyang
authors: L
authors: Dian
authors: National Institute of Biological Sciences (NIBS), Beijing 102206, China.
authors: Xiuguo
authors: X
authors: Zhang
authors: National Institute of Biological Sciences (NIBS), Beijing 102206, China.
authors: Lin
authors: L
authors: Li
authors: National Institute of Biological Sciences (NIBS), Beijing 102206, China.
authors: She
authors: S
authors: Chen
authors: National Institute of Biological Sciences (NIBS), Beijing 102206, China.
authors: Ran
authors: R
authors: Cao
authors: National Institute of Biological Sciences (NIBS), Beijing 102206, China.
authors: Li
authors: L
authors: Li
authors: National Institute of Biological Sciences (NIBS), Beijing 102206, China.
authors: Niu
authors: N
authors: Huang
authors: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, China.
authors: Sudan
authors: S
authors: He
authors: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.|National Institute of Biological Sciences (NIBS), Beijing 102206, China.|Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
authors: Xiaoguang
authors: X
authors: Lei
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D003545:Cysteine / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000187:drug effects* / Q000378:metabolism; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007783:Lactones; D016328:NF-kappa B; D012717:Sesquiterpenes; C530462:ainsliadimer A; D051550:I-kappa B Kinase; D003545:Cysteine