A novel selective ERK1/2 inhibitor, Laxiflorin B, targets EGFR mutation subtypes in non-small-cell lung cancer

• Published in: Acta pharmacologica Sinica 2024-02, Vol.45 (2), p.422-435
• Main Authors: Chiang, Cheng-Yao, Zhang, Min, Huang, Junrong, Zeng, Juan, Chen, Chunlan, Pan, Dongmei, Yang, Heng, Zhang, Tiantian, Yang, Min, Han, Qiangqiang, Wang, Zou, Xiao, Tian, Chen, Yangchao, Zou, Yongdong, Yin, Feng, Li, Zigang, Zhu, Lizhi, Zheng, Duo
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Computer Simulation; ErbB Receptors; Humans; Immunology; Intercellular Signaling Peptides and Proteins - metabolism; Internal Medicine; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; MAP Kinase Signaling System; Medical Microbiology; Mice; Mice, Nude; Mutation; Pharmacology/Toxicology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-023-01164-w

Extracellular regulated protein kinases 1/2 (ERK1/2) are key members of multiple signaling pathways, including the ErbB axis. Ectopic ERK1/2 activation contributes to various types of cancer, especially drug resistance to inhibitors of RTK, RAF and MEK, and specific ERK1/2 inhibitors are scarce. In this study, we identified a potential novel covalent ERK inhibitor, Laxiflorin B, which is a herbal compound with anticancer activity. However, Laxiflorin B is present at low levels in herbs; therefore, we adopted a semi-synthetic process for the efficient production of Laxiflorin B to improve the yield. Laxiflorin B induced mitochondria-mediated apoptosis via BAD activation in non-small-cell lung cancer (NSCLC) cells, especially in EGFR mutant subtypes. Transcriptomic analysis suggested that Laxiflorin B inhibits amphiregulin (AREG) and epiregulin (EREG) expression through ERK inhibition, and suppressed the activation of their receptors, ErbBs, via a positive feedback loop. Moreover, mass spectrometry analysis combined with computer simulation revealed that Laxiflorin B binds covalently to Cys-183 in the ATP-binding pocket of ERK1 via the D-ring, and Cys-178 of ERK1 through non-inhibitory binding of the A-ring. In a NSCLC tumor xenograft model in nude mice, Laxiflorin B also exhibited strong tumor suppressive effects with low toxicity and AREG and EREG were identified as biomarkers of Laxiflorin B efficacy. Finally, Laxiflorin B-4, a C-6 analog of Laxiflorin B, exhibited higher binding affinity for ERK1/2 and stronger tumor suppression. These findings provide a new approach to tumor inhibition using natural anticancer compounds.