Elkafoury, Eman M, El-Moselhy, Tarek F, El-Hamamsy, Mervat H, El-Bastawissy, Eman A, Rabea, Esraa Y, Afarinkia, Kamyar ORCID: https://orcid.org/0000-0003-2819-4364 and Sidhom, Peter A (2026) Single versus dual EGFR/PARP inhibition: Mechanistic rationale, synthetic approaches, pharmacophoric features, structure–activity relationships, and therapeutic perspectives. European Journal of Medicinal Chemistry, 316. ISSN 0223-5234

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Abstract

Cancer remains a major global health challenge, driving the need for more effective targeted therapies. Simultaneous inhibition of the epidermal growth factor receptor (EGFR) and poly(ADP-ribose) polymerase (PARP) has emerged as a promising strategy due to the strong interplay between oncogenic signaling and DNA repair pathways. Although EGFR inhibitors, PARP inhibitors, and multitarget-directed ligands have been widely reviewed individually, a focused medicinal chemistry perspective on dual EGFR/PARP inhibitors remains limited. This review specifically highlights the rational design of dual EGFR/PARP inhibitors, emphasizing pharmacophore fusion, linker engineering, scaffold optimization, and structure–activity relationship (SAR) studies governing balanced dual-target activity. Particular attention is given to quinazoline-, quinoline-, pyrimidine- and nicotinamide-based scaffolds, synthetic strategies for hybrid molecule construction, and the molecular determinants influencing potency, and selectivity. In addition, molecular docking and computational studies are discussed to clarify dual binding interactions within EGFR and PARP active sites. Emerging multifunctional systems integrating EGFR inhibition, PARP suppression, and DNA-damaging capabilities are also summarized as advanced anticancer approaches.

Item Type:	Article
Identifier:	10.1016/j.ejmech.2026.119047
Keywords:	Cancer; Dual inhibitors; PARP; EGFR
Subjects:	Natural sciences > Cell and molecular biology Medicine and health > Clinical medicine
Date Deposited:	02 Sep 2026
Dates:	Date Publication status 6 June 2026 Accepted 8 June 2026 Published Online
School, department or research centre:	School of Medicine and Biosciences
Keywords:	Cancer; Dual inhibitors; PARP; EGFR
URI:	https://repository.uwl.ac.uk/id/eprint/15289

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