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

We previously described the discovery of carbamate-derived small molecules as potent and selective lysophosphatidic acid receptor 1 (LPA 1 ) antagonists. To further expand the library of LPA 1 antagonists and potentially enhance their stability and potency, a urea moiety was introduced in replacement of the carbamate group and a series of LPA 1 antagonists based on a urea scaffold were synthesized and evaluated. Within this series, several compounds exhibited potent LPA 1 antagonism. Notably, compound 5f emerged as one of the most potent, with an IC 50 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 LPA 1 . The development of these urea-derived LPA 1 antagonists in this study has expanded the repertoire of LPA 1 antagonists and holds potential for the development of a novel therapy for metastatic triple-negative breast cancer. • A potent and selective lysophosphatidic acid receptor 1 (LPA₁) antagonist has been identified. • LPA₁ antagonists are proposed as a new class of migrastatic drugs targeting cancer metastasis. • The LPA₁ antagonist inhibits cancer cell invasion and migration independently of effects on proliferation and apoptosis.