JCN037 is a Non-Covalent and Brain-Penetrant EGFR Inhibitor
Posted On 2020-06-24
The epidermal growth factor receptor (EGFR) is a transmembrane protein that is a receptor for members of the EGF family of extracellular protein ligands. In many cancer types, mutations affecting EGFR expression or activity could result in cancer. Specifically, EGFR gene changes occurred in nearly 60% of glioblastoma tumors. Besides, the rest of the tumors in the cohort had amplification of active extracellular domain mutations. Moreover, the expanded wtEGFR and EGFRvIII play an important role in tumor growth, proliferation, and survival. Furthermore, wtEGFR is expressed in tumors expressing egfrv3 and cooperates with egfrv3 to promote tumorigenesis. There is a large amount of evidence that none of the first-generation EGFR TKI passes through the blood-brain barrier (BBB) at a concentration. And it is not sufficient to achieve a therapeutic effect in GBM tumors. JCN037 is a potent, non-covalent, and brain-penetrant EGFR tyrosine kinase inhibitor.
JCN037 is a potent, non-covalent, and brain-penetrant EGFR tyrosine kinase inhibitor.
How does JCN037 work on the target? Let’s study it together. In the beginning, JCN037 (JGK037) is a potent, non-covalent and brain-penetrant EGFR tyrosine kinase inhibitor. Meanwhile, JCN037 has IC50 values of 2.49 nM, 3.95 nM, 4.48 nM for EGFR, p-wtEGFR and pEGFRvⅢ, respectively. Nonetheless, JCN037 exhibits GI50 values of 329 nM and 1116 nM in HK301 cells and GBM39 cells, respectively.
In addition, JCN037 downregulated pEGFRvⅢ, p Akt, p-ERK, and p-S6 protein levels, significantly. Importantly, JCN037 exhibits low oral bioavailability due to a rapid hydroxylation of the fused 1,4-dioxane ring, suggesting first pass metabolism. By the way, JCN037 provides a significant survival benefit, whereby median survival increased by 47% from 37.5 days to 55 days with 5 treatment.
All in all, JCN037 is a potent, non-covalent, and brain-penetrant EGFR tyrosine kinase inhibitor.
Jonathan E. Tsang, et al. ACS Med. Chem. Lett. 2020. May 1.