TY - JOUR
T1 - Discovery of Protease-activated receptor 2 antagonists derived from phenylalanine for the treatment of breast cancer
AU - Kim, Taegun
AU - Lee, Yechan
AU - Lim, Hocheol
AU - Kim, Yeonhwa
AU - Cho, Haeun
AU - Namkung, Wan
AU - Han, Gyoonhee
N1 - Publisher Copyright:
© 2024 Elsevier Inc.
PY - 2024/9
Y1 - 2024/9
N2 - 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.
AB - 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.
KW - Breast cancer
KW - ERK1/2
KW - In silico docking simulation
KW - Protease-activated receptor 2
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U2 - 10.1016/j.bioorg.2024.107496
DO - 10.1016/j.bioorg.2024.107496
M3 - Article
C2 - 38850590
AN - SCOPUS:85195320159
SN - 0045-2068
VL - 150
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 107496
ER -