LPA1 Antagonists as Potential Migrastatics for Triple Negative Breast Cancer

Metastasis accounts for roughly 90% of cancer-related deaths. A new type of Anti-metastatic agents, known as migrastatics, offer a new therapeutic strategy that targets solely cancer cell migration and invasion while sparing proliferation. The FDA’s introduction of metastasis-free survival as a clinical endpoint in 2018 has created a regulatory framework that supports the development of such agents. By limiting cellular motility rather than inducing cytotoxic stress, migrastatics are expected to impose minimal selective pressure for the emergence of aggressive, drug-resistant subclones. Lysophosphatidic Acid Receptor 1 (LPA1), activated by the endogenous lipid LPA, is a key mediator of metastatic progression in triple-negative breast cancer (TNBC) and several other malignancies. We observed that LPA1 expression in MDA-MB-231 TNBC cells is at least 5-fold higher than in the non-malignant breast epithelial line MCF10A, supporting its role as a viable migrastatic target. Here, we report our medicinal chemistry efforts toward the discovery of novel LPA1 antagonists as potential migrastatic agents for TNBC. The lead compounds identified demonstrate high selectivity and potency, with IC50 values ranging from 16.0 to 107 nM in a cAMP assay and no detectable activity at LPA2 or LPA3. These compounds suppress TNBC cell survival, migration, and invasion without inducing apoptosis or cytotoxicity. These findings are consistent with the mechanistic expectations of migrastatic therapy and support further preclinical development of LPA1-targeted agents for metastatic TNBC. In vivo efficacy and toxicity studies are currently underway. Citation Format: Wenjie Liu, Kelsie L. Thu, Jinqiang Hou. LPA1 antagonists as potential migrastatics for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7491.