A Novel Selective ERK1/2 Inhibitor, Laxiflorin B, Targets EGFR Mutation Subtypes in Non-small-cell Lung Cancer

Chengyao Chiang, Min Zhang, Junrong Huang, Juan Zeng, Chunlan Chen, Dongmei Pan, Heng Yang, Min Yang, Qiangqiang Han, Wang Zou, Tian Xiao, Yongdong Zou, Feng Yin, Zigang Li, Lizhi Zhu, Duo Zheng
2022 · doi:10.1101/2022.06.27.497627
preprint OA: closed CC-BY-NC-ND-4.0
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Abstract

Extracellular regulated protein kinases 1/2 (ERK1/2) are key members of multiple signaling pathways including the ErbB axis. ERK1/2 ectopic activation is responsible for various types of cancer, especially drug resistance to inhibitors of RTK, RAF and MEK, but specific ERK1/2 inhibitors are scarce. In this study, we identified a potential novel ERK covalent inhibitor, Laxiflorin B, 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. More importantly, mass spectrometry combined with computer simulation analysis revealed that Laxiflorin B binds covalently to Cys-183 in the ATP-binding pocket of ERK1 through D-ring, and Cys-178 of ERK1 though non-inhibitory binding of A-ring, respectively. Laxiflorin B also exhibited strong tumor suppressive effects with low toxicity in a NSCLC tumor xenograft model in nude mice, and AREG and EREG were identified as biomarkers of Laxiflorin B efficacy. Finally, Laxiflorin B-4, a C-6 modification of Laxiflorin B, exhibited higher affinity for ERK1/2 and stronger tumor suppression. These findings provide a new approach to tumor inhibition using natural anticancer compounds.

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License: CC-BY-NC-ND-4.0