title: Selective targeting p53WTlung cancer cells harboring homozygous p53 Arg72 by an inhibitor of CypA.
abstract: TP53 plays essential roles in tumor initiation and progression, and is frequently mutated in cancer. However, pharmacological stabilization and reactivation of p53 have not been actively explored for targeted cancer therapies. Herein, we identify a novel Cyclophilin A (CypA) small molecule inhibitor (HL001) that induces non-small cell lung cancer (NSCLC) cell cycle arrest and apoptosis via restoring p53 expression. We find that HL001 stabilizes p53 through inhibiting the MDM2-mediated p53 ubiquitination. Further mechanistic studies reveal that the downregulation of G3BP1 and the induction of reactive oxygen species and DNA damage by HL001 contribute to p53 stabilization. Surprisingly, HL001 selectively suppresses tumor growth in p53 wild-type NSCLC harboring Arg72 homozygous alleles (p53-72R) through disrupting interaction between MDM2 and p53-72R in a CypA-dependent manner. Moreover, combining HL001 with cisplatin synergistically enhance tumor regression in orthotopic NSCLC mouse model. Collectively, this study demonstrates that pharmacologic inhibition of CypA offers a potential therapeutic strategy via specific activation of p53-72R in NSCLC.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: W
authors.initials: W
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China.
authors.forename: F
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: W
authors.initials: W
authors.lastname: Yan
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Yao
authors.affiliation: Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Song
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Shen
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.|CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Cell and Development Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D021984:Cyclophilin A / Q000037:antagonists & inhibitors*; D004265:DNA Helicases; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005449:Fluorenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006720:Homozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D000075223:Poly-ADP-Ribose Binding Proteins; D055550:Protein Stability / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D005449:Fluorenes; C000623148:HL001 compound; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D016159:Tumor Suppressor Protein p53; D014508:Urea; D051736:Proto-Oncogene Proteins c-mdm2; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases; D021984:Cyclophilin A; D002945:Cisplatin