title: Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein.
abstract: We report the development of novel Mixed Lineage Kinase Domain-Like protein (MLKL) inhibitors with single nanomolar potency (compound 15 is also named as TC13172). Using the converting biochemistry to chemistry activity-based protein profiling (BTC-ABPP) method, we were able to determine that the inhibitors covalently bind to Cysteine86 (Cys-86) of MLKL. This is the first example of the use of LC-MS/MS to identify the binding site of an MLKL inhibitor. The novel MLKL inhibitors provide powerful tools to study the biological function of MLKL and demonstrate that MLKL should be viewed as a druggable target.
authors.affiliation: School of Life Sciences, Peking University, Beijing, 100871, China and National Institute of Biological Sciences, Beijing, 102206, China. wangxiaodong@nibs.ac.cn zhangzhiyuan@nibs.ac.cn.
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.affiliation: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China and National Institute of Biological Sciences, Beijing, 102206, China. wangxiaodong@nibs.ac.cn zhangzhiyuan@nibs.ac.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, China. wangxiaodong@nibs.ac.cn zhangzhiyuan@nibs.ac.cn.
authors.forename: Shaoqiang
authors.initials: S
authors.lastname: Huang
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, China. wangxiaodong@nibs.ac.cn zhangzhiyuan@nibs.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ren
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, China. wangxiaodong@nibs.ac.cn zhangzhiyuan@nibs.ac.cn.
authors.forename: Huayi
authors.initials: H
authors.lastname: Wang
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, China. wangxiaodong@nibs.ac.cn zhangzhiyuan@nibs.ac.cn.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yao
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, China. wangxiaodong@nibs.ac.cn zhangzhiyuan@nibs.ac.cn.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, China. wangxiaodong@nibs.ac.cn zhangzhiyuan@nibs.ac.cn.
authors.forename: She
authors.initials: S
authors.lastname: Chen
authors.affiliation: Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China and National Institute of Biological Sciences, Beijing, 102206, China. wangxiaodong@nibs.ac.cn zhangzhiyuan@nibs.ac.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Institute of Biological Sciences, Beijing, 102206, China. wangxiaodong@nibs.ac.cn zhangzhiyuan@nibs.ac.cn and Collaborative Innovation Center for Cancer Medicine, Beijing, 102206, China.
authors.forename: Zhiyuan
authors.identifier: http://orcid.org/0000-0002-2910-1986
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D009336:Necrosis / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; C570693:MLKL protein, human; D011494:Protein Kinases