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

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

  • Acta Pharmacol Sin. 2023 Oct 10. doi: 10.1038/s41401-023-01164-w.
Cheng-Yao Chiang # 1,  Min Zhang # 1,  Junrong Huang # 1,  Juan Zeng # 2,  Chunlan Chen 1,  Dongmei Pan 1,  Heng Yang 1,  Tiantian Zhang 1,  Min Yang 1,  Qiangqiang Han 3 4,  Zou Wang 4,  Tian Xiao 1,  Yangchao Chen 5,  Yongdong Zou 1,  Feng Yin 6,  Zigang Li 6,  Lizhi Zhu 7 8,  Duo Zheng 9
Affiliations

Affiliations

  • 1 Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, International Cancer Center, Department of Cell Biology and Genetics, Shenzhen University Medical School; College of Life Sciences and Oceanography, Shenzhen University; Department of Pharmacy, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518055, China.
  • 2 School of Biomedical Engineering, Guangdong Medical University, Dongguan, 523808, China.
  • 3 SpecAlly Life Technology Co., Ltd, Wuhan, 430075, China.
  • 4 Wuhan Biobank Co., Ltd, Wuhan, 430074, China.
  • 5 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
  • 6 Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen University Town, Xili, Shenzhen, 518055, China.
  • 7 Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, International Cancer Center, Department of Cell Biology and Genetics, Shenzhen University Medical School; College of Life Sciences and Oceanography, Shenzhen University; Department of Pharmacy, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518055, China. [email protected].
  • 8 Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen, 518035, China. [email protected].
  • 9 Guangdong Key Laboratory of Genome Instability and Human Disease Prevention, International Cancer Center, Department of Cell Biology and Genetics, Shenzhen University Medical School; College of Life Sciences and Oceanography, Shenzhen University; Department of Pharmacy, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518055, China. [email protected].
  • # Contributed equally.
PMID: 37816856 DOI: 10.1038/s41401-023-01164-w
Abstract

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.

Keywords

AREG; EREG; ERK1/2; NSCLC; laxiflorin B; natural compound.

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