2. Academic Validation
  3. Identification of a small-molecule compound that inhibits homodimerization of oncogenic NAC1 protein and sensitizes cancer cells to anticancer agents

Identification of a small-molecule compound that inhibits homodimerization of oncogenic NAC1 protein and sensitizes cancer cells to anticancer agents

  • J Biol Chem. 2019 Jun 21;294(25):10006-10017. doi: 10.1074/jbc.RA119.007664.
XiaoHui Wang 1,  Cheng Ji 2,  HongHan Zhang 1,  Yu Shan 3,  YiJie Ren 1,  YanWei Hu 1,  LiangRong Shi 4,  LingChuan Guo 1,  WeiDong Zhu 1,  YuJuan Xia 1,  BeiJia Liu 1,  ZiYun Rong 1,  BiLian Wu 1,  ZhiJun Ming 1,  XingCong Ren 5,  JianXun Song 6,  JinMing Yang 7,  Yi Zhang 8
Affiliations

Affiliations

  • 1 From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China.
  • 2 Department of Respiratory Medicine, First Affiliated Hospital, Soochow University, 215000 Suzhou, Jiangsu, China.
  • 3 Institute of Botany, Jiangsu Province and Chinese Academy of Science, 210014 Nanjing, Jiangsu, China.
  • 4 Radiological Intervention Center, Department of Radiology, Xiangya Hospital, Central South University, 410013 Changsha, Hunan, China.
  • 5 Department of Cancer Biology and Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40506.
  • 6 Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, College Station, Texas 77843, and.
  • 7 Department of Cancer Biology and Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40506 jyang@uky.edu.
  • 8 From the Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, Jiangsu, China, zhangyi@suda.edu.cn.
PMID: 31101655 DOI: 10.1074/jbc.RA119.007664
Abstract

Nucleus accumbens-associated protein-1 (NAC1) is a transcriptional repressor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive. In this study, we identified a core unit consisting of Met7 and Leu90 in NAC1's N-terminal domain (Amino acids 1-130), which is critical for its homodimerization and stability. Furthermore, using a combination of computational analysis of the NAC1 dimerization interface and high-throughput screening (HTS) for small molecules that inhibit NAC1 homodimerization, we identified a compound (NIC3) that selectively binds to the conserved Leu-90 of NAC1 and prevents its homodimerization, leading to proteasomal NAC1 degradation. Moreover, we demonstrate that NIC3-mediated down-regulation of NAC1 protein sensitizes drug-resistant tumor cells to conventional chemotherapy and enhances the antimetastatic effect of the antiangiogenic agent bevacizumab both in vitro and in vivo These results suggest that small-molecule inhibitors of NAC1 homodimerization may effectively sensitize Cancer cells to some Anticancer agents and that NAC1 homodimerization could be further explored as a potential therapeutic target in the development of antineoplastic agents.

Keywords

NAC1; cancer biology; cancer therapy; combination therapy; dimerization; inhibitor; protein targeting; transcription target gene.

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