Development of UTX-143, a selective sodium-hydrogen exchange subtype 5 inhibitor, using amiloride as a lead compound

  • Bioorg Med Chem. 2024 Feb 1:99:117603. doi: 10.1016/j.bmc.2024.117603.
Yusei Shinohara  1 ,  Yuki Komiya  1 ,  Kashin Morimoto  1 ,  Yoshio Endo  2 ,  Minoru Terashima  3 ,  Takeshi Suzuki  3 ,  Takahisa Takino  4 ,  Itasu Ninomiya  5 ,  Hisatsugu Yamada  1 ,  Yoshihiro Uto  6
Affiliations
  • 1. Graduate School of Technology, Industrial and Social Science, Tokushima University, Minamijosanjimacho-2, Tokushima 770-8506, Japan.
  • 2. Central Research Resource Branch, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
  • 3. Division of Functional Geneomics, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
  • 4. Division of Education for Global Standard, Institute of Liberal Arts and Science, Kanazawa University Kakuma-machi, Kanazawa 920-1192, Japan.
  • 5. Director of Central Medical Center and Department of Surgery, Fukui Prefectural Hospital, Yotsui-2, Fukui 910-0846, Japan.
  • 6. Graduate School of Technology, Industrial and Social Science, Tokushima University, Minamijosanjimacho-2, Tokushima 770-8506, Japan. Electronic address: [email protected].
PMID: 38246115 DOI: 10.1016/j.bmc.2024.117603
Abstract

NHE5, an isoform of the Na+/H+ exchanger (NHE) protein, is an ion-transporting membrane protein that regulates intracellular pH and is highly expressed in colorectal adenocarcinoma. Therefore, we hypothesized that NHE5 inhibitors can be used as Anticancer drugs. However, because NHE1 is ubiquitously expressed in all cells, it is extremely important to demonstrate its selective inhibitory activity against NHE5. We used amiloride, an NHE non-selective inhibitor, as a lead compound and created UTX-143, which has NHE5-selective inhibitory activity, using a structure-activity relationship approach. UTX-143 showed selective cytotoxic effects on Cancer cells and reduced the migratory and invasive abilities of Cancer cells. These results suggest a new concept wherein drugs exhibit cancer-specific cytotoxic effects through selective inhibition of NHE5 and the possibility of UTX-143 as a lead NHE5-selective inhibitor.

Keywords
Amiloride; Anti-invasion; Antitumor; NHE5 inhibitor; Structure-activity relationship.
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