title: Synthesis, molecular modeling, and biological evaluation of novel RAD51 inhibitors.
abstract: RAD51 recombinase plays a critical role for cancer cell proliferation and survival. Targeting RAD51 is therefore an attractive strategy for treating difficult-to-treat cancers, e.g. triple negative breast cancers which are often resistant to existing therapeutics. To this end, we have designed, synthesized and evaluated a panel of new RAD51 inhibitors, denoted IBR compounds. Among these compounds, we have identified a novel small molecule RAD51 inhibitor, IBR120, which exhibited a 4.8-fold improved growth inhibition activity in triple negative human breast cancer cell line MBA-MD-468. IBR120 also inhibited the proliferation of a broad spectrum of other cancer cell types. Approximately 10-fold difference between the IC50 values in normal and cancer cells were observed. Moreover, IBR120 was capable of disrupting RAD51 multimerization, impairing homologous recombination repair, and inducing apoptotic cell death. Therefore, these novel RAD51 inhibitors may serve as potential candidates for the development of pharmaceutical strategies against difficult-to-treat cancers.
authors: Department of Biological Chemistry, School of Medicine, USA.
authors: Jiewen
authors: J
authors: Zhu
authors: Department of Biological Chemistry, School of Medicine, USA.
authors: Hongyuan
authors: H
authors: Chen
authors: Department of Biological Chemistry, School of Medicine, USA.
authors: Xuning Emily
authors: XE
authors: Guo
authors: Department of Biological Chemistry, School of Medicine, USA.
authors: Xiao-Long
authors: XL
authors: Qiu
authors: Department of Biological Chemistry, School of Medicine, USA; Taiwan Genomic Research Center, Academia Sinica, Taipei, Taiwan.
authors: Chun-Mei
authors: CM
authors: Hu
authors: Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697, USA.
authors: A Richard
authors: AR
authors: Chamberlin
authors: Department of Biological Chemistry, School of Medicine, USA; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan. Electronic address: whlee@uci.edu.
authors: Wen-Hwa
authors: WH
authors: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D051135:Rad51 Recombinase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001593:Benzyl Compounds; C000606772:IBR120; D013844:Thiazoles; C495153:RAD51 protein, human; D051135:Rad51 Recombinase
keywords: Breast cancer; Indole alkaloid; QSAR; RAD51 inhibitor; Synthesis; Triple-negative