Discovery of new thieno[2,3- d]pyrimidines as EGFR tyrosine kinase inhibitors for cancer treatment

Eman A Sobh; Mohammed A Dahab; Eslam B Elkaeed; Aisha A Alsfouk; Ibrahim M Ibrahim; Ahmed M Metwaly; Ibrahim H Eissa

doi:10.4155/fmc-2023-0086

Discovery of new thieno[2,3- d]pyrimidines as EGFR tyrosine kinase inhibitors for cancer treatment

Future Med Chem. 2023 Jul;15(13):1167-1184. doi: 10.4155/fmc-2023-0086. Epub 2023 Aug 2.

Authors

Eman A Sobh¹, Mohammed A Dahab², Eslam B Elkaeed³, Aisha A Alsfouk⁴, Ibrahim M Ibrahim⁵, Ahmed M Metwaly^{6

7}, Ibrahim H Eissa²

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Menoufia University, Menoufia, Egypt.
² Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
³ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, 13713, Saudi Arabia.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, PO Box 84428, Riyadh, 11671, Saudi Arabia.
⁵ Biophysics Department, Faculty of Science, Cairo University, Cairo, 12613, Egypt.
⁶ Pharmacognosy & Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
⁷ Biopharmaceutical Products Research Department, Genetic Engineering & Biotechnology Research Institute, City of Scientific Research & Technological Applications (SRTA-City), Alexandria, 21934, Egypt.

PMID: 37529910
DOI: 10.4155/fmc-2023-0086

Abstract

Background: EGFR has been considered a vital molecular target in cancer management. Aim: The discovery of new thieno[2,3-d]pyrimidine derivatives as EGFR tyrosine kinase inhibitors. Methods: Nine derivatives were designed, synthesized and subjected to in vitro and in silico studies. Results: Compound 7a significantly inhibited the growth of HepG2 and PC3 cells for both EGFR wild-type and EGFR_T790M. Compound 7a caused a significant apoptotic effect, arresting HepG2 cells' growth in the S and G2/M phases. Docking and molecular dynamics simulation studies confirmed the correct and stable binding modes of the synthesized compounds against the active sites. Conclusion: Compound 7a is a promising dual EGFR inhibitor for cancer treatment.

Keywords: EGFR TKIs; MD simulations; anticancer; docking; thieno[2,3-d]pyrimidine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
ErbB Receptors
Humans
Lung Neoplasms*
Molecular Docking Simulation
Molecular Structure
Mutation
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Pyrimidines / chemistry
Pyrimidines / pharmacology
Structure-Activity Relationship
Tyrosine Kinase Inhibitors

Substances

ErbB Receptors
Tyrosine Kinase Inhibitors
Pyrimidines
Protein Kinase Inhibitors
Antineoplastic Agents
EGFR protein, human