Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors
Milik, Sandra N; Abdel-Aziz, Amal Kamal; Serya, Rabah; Minucci, Saverio; Lasheen, Deena S.; Khaled A M Abouzid;
Abstract
In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3-d]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC50 values of 91.7 nM and 1.2 μM, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC50 values of 1.45, 3.5 and 4.83 μM, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC50 of 4.2 μM. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance.
Other data
Title | Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors | Authors | Milik, Sandra N; Abdel-Aziz, Amal Kamal; Serya, Rabah ; Minucci, Saverio; Lasheen, Deena S. ; Khaled A M Abouzid | Keywords | Dual EGFR/HER2 inhibitors;Thieno[2,3-d]pyrimidine;EGFR inhibitors resistance | Issue Date | 15-Jul-2018 | Publisher | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER | Journal | European Journal of Medicinal Chemistry | Volume | 155 | Start page | 316 | End page | 336 | ISSN | 0223-5234 | DOI | 10.1016/j.ejmech.2018.06.011 | PubMed ID | 29902719 | Scopus ID | 2-s2.0-85048294666 | Web of science ID | WOS:000441856300025 |
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