Discovery of Protease-activated receptor 2 antagonists derived from phenylalanine for the treatment of breast cancer

• Published in: Bioorganic chemistry Vol. 150; p. 107496
• Main Authors: Kim, Taegun, Lee, Yechan, Lim, Hocheol, Kim, Yeonhwa, Cho, Haeun, Namkung, Wan, Han, Gyoonhee
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2024
• Subjects: Breast cancer; ERK1/2; In silico docking simulation; Protease-activated receptor 2; ERK1/2; YFP; In silico docking simulation; PAR2-AP; PAR2; SAR; GPCR; Breast cancer; MAPK; Protease-activated receptor 2; ERK
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107496

[Display omitted] •Phe(F)-derived 1c synthesized from 2-phenyloxazol-5(4H)-one showed PAR2 antagonism.•Through SAR analysis supported by docking simulation, 9a which is a more potent antagonist than 1c was discovered.•9a and 9d showed opposite activities as PAR2 antagonist and agonist, respectively.•MD simulations were employed to elucidate the opposing effects of 9a and 9d. Protease-activated receptor 2 (PAR2) has garnered attention as a potential therapeutic target in breast cancer. PAR2 is implicated in the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) via G protein and beta-arrestin pathways, contributing to the proliferation and metastasis of breast cancer cells. Despite the recognized role of PAR2 in breast cancer progression, clinically effective PAR2 antagonists remain elusive. To address this unmet clinical need, we synthesized and evaluated a series of novel compounds that target the orthosteric site of PAR2. Using in silico docking simulations, we identified compound 9a, an optimized derivative of compound 1a ((S)-N-(1-(benzylamino)-1-oxo-3-phenylpropan-2-yl)benzamide), which exhibited enhanced PAR2 antagonistic activity. Subsequent molecular dynamics simulations comparing 9a with the partial agonist 9d revealed that variations in ligand-induced conformational changes and interactions dictated whether the compound acted as an antagonist or agonist of PAR2. The results of this study suggest that further development of 9a could contribute to the advancement of PAR2 antagonists as potential therapeutic agents for breast cancer.