Discovery of novel Macrocyclic small molecules Based on 2-Amino-4-thiazolylpyridineas selective EGFR inhibitors with high Blood-Brain barrier penetration for the treatment of glioblastoma.

Because epidermal growth factor receptor (EGFR) is the most commonly mutated oncogene in glioblastoma (GBM), the development of EGFR inhibitors has become a promising direction for the treatment of GBM. However, due to factors such as limited blood-brain barrier (BBB) permeability and pathway compensation mechanisms, current EGFR inhibitors targeting GBM are not satisfactory. In the previous study, we obtained compound 10c with strong anti-cell proliferation activity. Since macrocyclization can effectively change the physical and chemical properties of molecules, and optimize their selectivity. Therefore, a series of 2-amino-4-thiazolyl pyridine scaffold macrocyclic derivatives were designed and synthesized using compound 10c as the lead compound in this study. Compound 3a, which inhibited the growth of glioblastoma cell lines U87MG and U87-EGFRVIII, had average IC50 values of 4.69 µM and 4.98 µM, respectively. Compound 3a was highly selective to 9 kinases in the ErbB family, including ErbB2 and ErbB4. In addition, compound 3a demonstrated good blood-brain barrier permeability in mice, the blood-brain concentration of the drug remained above 20 % within 5-60 min following intravenous administration in mice. In conclusion, compound 3a is a promising candidate for novel EGFR inhibitors targeting GBM.