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  3. Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors

Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors

  • Eur J Med Chem. 2018 Jul 15:155:316-336. doi: 10.1016/j.ejmech.2018.06.011.
Sandra N Milik 1,  Amal Kamal Abdel-Aziz 2,  Deena S Lasheen 3,  Rabah A T Serya 3,  Saverio Minucci 4,  Khaled A M Abouzid 5
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt. Electronic address: Sandra.milik3@pharma.asu.edu.eg.
  • 2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt; Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139, Milan, Italy.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt.
  • 4 Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139, Milan, Italy; Department of Biosciences, University of Milan, Milan, 20100, Italy.
  • 5 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt. Electronic address: khaled.abouzid@pharma.asu.edu.eg.
PMID: 29902719 DOI: 10.1016/j.ejmech.2018.06.011
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.

Keywords

Dual EGFR/HER2 inhibitors; EGFR inhibitors resistance; Thieno[2,3-d]pyrimidine.

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