2. Academic Validation
  3. Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR inhibitors

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

  • Bioorg Med Chem. 2018 May 1;26(8):2173-2185. doi: 10.1016/j.bmc.2018.03.025.
Yuan-Yuan Hei 1,  Ying Shen 1,  Jin Wang 2,  Hao Zhang 1,  Hong-Yi Zhao 1,  Minhang Xin 1,  Yong-Xiao Cao 2,  Yan Li 1,  San-Qi Zhang 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
  • 2 Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: sqzhang@xjtu.edu.cn.
PMID: 29576272 DOI: 10.1016/j.bmc.2018.03.025
Abstract

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 EGFRL858R. Compound C12 showed moderate inhibitory activity against EGFRL858R/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.

Keywords

Anticancer agent; Antiproliferative effects; Drug design; EGFR-TK inhibitor; Purine.

Figures