2. Academic Validation
  3. Urea-based lysophosphatidic acid receptor 1 antagonists as potential migrastatics for triple-negative breast cancer

Urea-based lysophosphatidic acid receptor 1 antagonists as potential migrastatics for triple-negative breast cancer

  • Bioorg Chem. 2026 Jul 5:175:109807. doi: 10.1016/j.bioorg.2026.109807.
Wenjie Liu 1,  Amr A K Mousa 2,  Guillem Dayer 3,  Austin M Hopkins 1,  Michael Campbell 1,  Yang Mao 1,  Zi-Hua Jiang 4,  Simon J Lees 5,  Rithwik Ramachandran 2,  Jinqiang Hou 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Lakehead University, 955 Oliver Rd, Thunder Bay, ON P7B 5E1, Canada; Thunder Bay Regional Health Research Institute, 980 Oliver Road, Thunder Bay, ON P7B 6V4, Canada.
  • 2 Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
  • 3 Thunder Bay Regional Health Research Institute, 980 Oliver Road, Thunder Bay, ON P7B 6V4, Canada; Department of Biology, Lakehead University, Thunder Bay, ON, Canada.
  • 4 Department of Chemistry, Lakehead University, 955 Oliver Rd, Thunder Bay, ON P7B 5E1, Canada.
  • 5 Medical Sciences Division, Northern Ontario School of Medicine University, Thunder Bay, ON, Canada.
  • 6 Department of Chemistry, Lakehead University, 955 Oliver Rd, Thunder Bay, ON P7B 5E1, Canada; Thunder Bay Regional Health Research Institute, 980 Oliver Road, Thunder Bay, ON P7B 6V4, Canada. Electronic address: jhou3@lakeheadu.ca.
PMID: 41911633 DOI: 10.1016/j.bioorg.2026.109807
Abstract

We previously described the discovery of carbamate-derived small molecules as potent and selective lysophosphatidic acid receptor 1 (LPA1) antagonists. To further expand the library of LPA1 antagonists and potentially enhance their stability and potency, a urea moiety was introduced in replacement of the carbamate group and a series of LPA1 antagonists based on a urea scaffold were synthesized and evaluated. Within this series, several compounds exhibited potent LPA1 antagonism. Notably, compound 5f emerged as one of the most potent, with an IC50 of 215.2 nM in the cAMP assay and 7.9 nM in the calcium mobilization assay. Compound 5f demonstrated the ability to block LPA-induced cell migration and invasion in the triple-negative breast Cancer cell line MDA-MB-231. These findings support further in vivo evaluation of compound 5f as a potential therapeutic agent targeting LPA1. The development of these urea-derived LPA1 antagonists in this study has expanded the repertoire of LPA1 antagonists and holds potential for the development of a novel therapy for metastatic triple-negative breast Cancer.

Keywords

Lysophosphatidic acid receptor 1; Migrastatics; Triple-negative breast cancer; Urea.

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