2. Academic Validation
  3. Synthesis and biological evaluation of novel Ani9 derivatives as potent and selective ANO1 inhibitors

Synthesis and biological evaluation of novel Ani9 derivatives as potent and selective ANO1 inhibitors

  • Eur J Med Chem. 2018 Dec 5:160:245-255. doi: 10.1016/j.ejmech.2018.10.002.
Yohan Seo 1,  Jinhwang Kim 2,  Jiwon Chang 2,  Seong Soon Kim 3,  Wan Namkung 4,  Ikyon Kim 5
Affiliations

Affiliations

  • 1 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea; Interdisciplinary Program of Integrated OMICS for Biomedical Science Graduate School, Yonsei University, Seoul, 03722, Republic of Korea.
  • 2 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea.
  • 3 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 4 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea; Interdisciplinary Program of Integrated OMICS for Biomedical Science Graduate School, Yonsei University, Seoul, 03722, Republic of Korea. Electronic address: wnamkung@yonsei.ac.kr.
  • 5 College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon, 21983, Republic of Korea. Electronic address: ikyonkim@yonsei.ac.kr.
PMID: 30347323 DOI: 10.1016/j.ejmech.2018.10.002
Abstract

Anoctamin 1 (ANO1), a calcium-activated Chloride Channel, is highly expressed and amplified in a number of carcinomas including breast, pancreatic and prostate cancers. Downregulation of ANO1 expression and function significantly inhibits cell proliferation, migration, and invasion of various Cancer cell lines. Development of potent and selective ANO1 inhibitors is currently desirable, which may provide a new strategy for Cancer treatment. Our previous study revealed a new class of ANO1 inhibitor, (E)-2-(4-chloro-2-methylphenoxy)-N'-(2-methoxybenzylidene)acetohydrazide (Ani9) and structural optimization via chemical modification of Ani9 basic skeleton was undertaken for the development of more potent and specific inhibitors of ANO1. Structure-activity relationship studies with newly synthesized derivatives revealed a number of potent ANO1 inhibitors, among which 5f is the most potent inhibitor with an IC50 value of 22 nM. The selectivity analyses showed that 5f has excellent selectivity to ANO1 (>1000-fold over ANO2). In cellular assays, 5f significantly inhibited cell proliferation of PC3, MCF7, and BxPC3 cells expressing high levels of ANO1. In addition, 5f strongly reduced the protein levels of ANO1 in PC3 cells. This study will be useful in the development of ANO1 inhibitors for treatment of Cancer and other ANO1-related diseases.

Keywords

Ani9; Anoctamin 1 (ANO1); Anticancer agent; Structural modification; Structure-activity relationship.

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