title: A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia.
abstract: RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug-resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML). Directly targeting RAD51 and attenuating the deregulated RAD51 activity has therefore been proposed as an alternative and supplementary strategy for cancer treatment. Here we show that a newly identified small molecule, IBR2, disrupts RAD51 multimerization, accelerates proteasome-mediated RAD51 protein degradation, reduces ionizing radiation-induced RAD51 foci formation, impairs HR, inhibits cancer cell growth and induces apoptosis. In a murine imatinib-resistant CML model bearing the T315I Bcr-abl mutation, IBR2, but not imatinib, significantly prolonged animal survival. Moreover, IBR2 effectively inhibits the proliferation of CD34(+) progenitor cells from CML patients resistant to known BCR-ABL inhibitors. Therefore, small molecule inhibitors of RAD51 may suggest a novel class of broad-spectrum therapeutics for difficult-to-treat cancers.
authors: Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA.
authors: Jiewen
authors: J
authors: Zhu
authors: Longen
authors: L
authors: Zhou
authors: Guikai
authors: G
authors: Wu
authors: Heiko
authors: H
authors: Konig
authors: Xiaoqin
authors: X
authors: Lin
authors: Guideng
authors: G
authors: Li
authors: Xiao-Long
authors: XL
authors: Qiu
authors: Chi-Fen
authors: CF
authors: Chen
authors: Chun-Mei
authors: CM
authors: Hu
authors: Erin
authors: E
authors: Goldblatt
authors: Ravi
authors: R
authors: Bhatia
authors: A Richard
authors: AR
authors: Chamberlin
authors: Phang-Lang
authors: PL
authors: Chen
authors: Wen-Hwa
authors: WH
authors: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D062105:Molecular Docking Simulation; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C551678:(R)-1-(1H-indol-3-yl)-2-phenylmethanesulfonyl-1,2,3,4-tetrahydroisoquinoline; D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D044005:Tetrahydroisoquinolines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D046988:Proteasome Endopeptidase Complex