Design, synthesis and evaluation of new thiazolidin-4-ones as LPA<sub>1</sub> receptor antagonists for breast cancer therapy
Creators: name: Bhagyalalitha, Meduri
name: SR, Pavan
name: Prabhu, Ashwini
name: HS, Akshatha
name: Kumar, Sethu Arun
name: Singh, Manisha
name: Pujar, Karthik G
name: Pujar, Gurubasavaraj Veeranna
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Cell Biology
subject: Molecular Biology
subject: Pharmacology
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Developmental Biology
subject: Cancer
subject: Plant Biology
subject: FOS: Biological sciences

description: <b>Aim:</b> Breast cancer has been a leading cause of mortality among women worldwide in recent years. Targeting the lysophosphatidic acid (LPA)–LPA<sub>1</sub> pathway using small molecules could improve breast cancer therapy. <b>Materials &amp; methods:</b> Thiazolidin-4-ones were developed and tested on MCF-7 cancer cells, and active compounds were analyzed for their effects on apoptosis, migration angiogenesis and LPA<sub>1</sub> protein and gene expression. <b>Results &amp; conclusion:</b> Compounds TZ-4 and TZ-6 effectively reduced the migration of MCF-7 cells, and induced apoptosis. TZ-4, TZ-6, TZ-8 and TZ-14 significantly reduced the LPA<sub>1</sub> protein, LPA<sub>1</sub> and angiogenesis gene expression in treated MCF-7 cells. Molecular docking and molecular dynamic simulation studies reveal the ligand interactions and stability of the LPA<sub>1</sub>–ligand complex. Developed thiazolidin-4-ones showed great potential as an LPA<sub>1</sub>-targeted approach to combating breast cancer. Breast cancer is a major cause of death for women worldwide. Using small molecules to target the lysophosphatidic acid (LPA)–LPA<sub>1</sub> pathway could improve breast cancer treatment. We tested a type of molecule called thiazolidin-4-ones on breast cancer cells in the lab. We looked at how these molecules affected cell death, movement, blood vessel growth and the activity of the LPA<sub>1</sub> gene and protein. Some of these molecules, such as TZ-4 and TZ-6, reduced the movement of cancer cells and caused them to die. They also decreased the levels of LPA<sub>1</sub> protein and gene activity in the cells. We used computer simulations to see how these molecules interacted with the LPA<sub>1</sub> protein. Our findings suggest that thiazolidin-4-ones could be a promising treatment for breast cancer by targeting LPA<sub>1</sub>. New thiazolidin-4-ones were tested on MCF-7 cells; active compounds were analyzed for effects on apoptosis, migration, angiogenesis and LPA<sub>1</sub> expression. TZ-4 and TZ-6 reduced MCF-7 migration and induced apoptosis. Novel thiazolidin-4-ones as LPA<sub>1</sub> inhibitors and their subsequent effects. The study focused on developing novel thiazolidin-4-one based lysophosphatidic acid receptor-1 (LPA<sub>1</sub>) inhibitors to target breast cancer. Compounds TZ-4, TZ-6, TZ-8 and TZ-14 reduced LPA<sub>1</sub> expression and were most effective against MCF-7 breast cancer cells, with low toxicity. All the designed molecules showed potential and stable interactions for amino acids of LPA<sub>1</sub> binding pocket with less binding energy compared to the co-crystal structure. The compounds TZ-4, TZ-6, TZ-8 and TZ-14 show promise as potential candidates for breast cancer therapy with a focus on LPA<sub>1</sub> modulation.