title: Selective TBK1/IKKi dual inhibitors with anticancer potency.
abstract: Increasing evidence suggests that the noncanonical IKKs play critical roles in tumor genesis and development, leading to the notion that noncanonical IKKs may be good targets for cancer therapy. Here, we demonstrate that although TBK1 is not overexpressed or constitutively activated in some tumor cells, targeting IKKi induces the activation of TBK1. Therefore, simultaneously targeting both kinases is necessary to efficiently suppress tumor cell proliferation. We show that three TBK1/IKKi dual inhibitors, which are based on a structurally rigid 2-amino-4-(3'-cyano-4'-pyrrolidine)phenyl-pyrimidine scaffold, potently inhibit cell viability in human breast, prostate and oral cancer cell lines. Treatment with these TBK1/IKKi dual inhibitors significantly impairs tumor development in xenograft and allograft mouse models. The anticancer function of these inhibitors may be partially due to their suppression of TBK1/IKKi-mediated AKT phosphorylation and VEGF expression. Most importantly, these TBK1/IKKi dual inhibitors have drug-like properties including low molecular weight, low cytochrome P450 inhibition and high metabolic stability. Therefore, our studies provide proof of concept for further drug discovery efforts that may lead to novel strategies and new therapeutics for the treatment of human cancer.
authors.affiliation: Department of Stomatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL.
authors.forename: Jijia
authors.initials: J
authors.lastname: Li
authors.forename: Jingjia
authors.initials: J
authors.lastname: Huang
authors.forename: Ji-Hak
authors.initials: JH
authors.lastname: Jeong
authors.forename: Sun-Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Rui
authors.initials: R
authors.lastname: Wei
authors.forename: Jieying
authors.initials: J
authors.lastname: Peng
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Luo
authors.forename: Yen Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Yangbo
authors.initials: Y
authors.lastname: Feng
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Luo
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008264:Macrophages; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C588322:200A compound; C588321:200B compound; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; C588323:SR8185 compound; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C403191:TBK1 protein, human; D051550:I-kappa B Kinase; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD
keywords: IKKi; TBK1; TBK1/IKKi inhibitor; cancer; therapy