Design and Synthesis of 4-Anilinothieno[2,3-d]pyrimidine-Based Compounds as Dual EGFR/HER-2 Inhibitors

作者：Abd El Hadi Soha R; Lasheen Deena S^*; Hassan Mahmoud A; Abouzid Khaled A M^*

来源：Archiv der Pharmazie, 2016, 349(11): 827-847.

DOI：10.1002/ardp.201600197

• Antiproliferative activity
• Docking study
• EGFR
• HER2 kinase
• Thienopyrimidine

Dual inhibition of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER-2) is an attractive cancer therapeutic approach. In this study, new series of 4-anilinothieno[2,3-d]pyrimidines were designed, synthesized, and tested as dual EGFR/HER-2 kinase inhibitors. Five compounds (8a, 8b, 8e-g) demonstrated low to submicromolar inhibition of both kinases with IC50 values of 1.2, 0.6, 0.3, 0.2, 0.4 mu M and 8.2, 3.4, 1.3, 0.5, 2.7 mu M for the EGFR and HER-2, respectively. Introduction of a 5,6-tetramethylene moiety into the thienopyrimidine core bearing a 4-(3-fluorobenzyloxy)-3-chloroaniline tail resulted in a favorable increase in both the EGFR and HER-2 inhibitory activities. Compound 8f (IC50 EGFR/HER-2: 0.2/0.5 mu M) also exhibited significant cell growth inhibition on some specific NCI cell lines, especially ovarian, breast, non-small-cell lung cancer, and renal cancer cell lines.

• 出版日期2016-11