Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR Inhibitors

Publication date: Available online 16 March 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Yuan-Yuan Hei, Ying Shen, Jin Wang, Hao Zhang, Hong-Yi Zhao, Minhang Xin, Yong-Xiao Cao, Yan Li, San-Qi Zhang
In present study, we described the synthesis and biological evaluation of a new class of EGFR inhibitors containing 2, 9-disubstituted 8-phenylthio/ phenylsulfinyl-9H-purine scaffold. Thirty-one compounds were synthesized. Among them, compound C9 displayed the IC50 of 29.4 nM against HCC827 cell line and 1.9 nM against EGFR^L858R. Compound C12 showed moderate inhibitory activity against EGFR^{L858R/T790M/C797S} (IC50 = 114 nM). Western bolt assay suggested that compound C9 significantly inhibited EGFR phosphorylation. In vivo test, compound C9 remarkably exhibited inhibitory effect on tumor growth at 5.0 mg/kg by oral administration in established nude mouse HCC827 xenograft model. These results indicate that the 2,9-disubstituted 8-phenylsulfinyl/phenylsulfinyl-9H-purine derivatives can act as potent EGFR(L858R) inhibitors and effective anticancer agents. Additionally, optimization of compound C12 may result in discovering the fourth-generation EGFR-TKIs.

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