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Aim: The aim of this study was to design and examine a novel epidermal growth factor receptor (EGFR) inhibitor with apoptotic properties by utilizing the essential structural characteristics of existing EGFR inhibitors as a foundation., Method: The study began with the natural alkaloid theobromine and developed a new semisynthetic derivative ( T-1-PMPA ). Computational ADMET assessments were conducted first to evaluate its anticipated safety and general drug-likeness. Deep density functional theory (DFT) computations were initially performed to validate the three-dimensional (3D) structure and reactivity of T-1-PMPA . Molecular docking against the EGFR proteins was conducted to investigate T-1-PMPA 's binding affinity and inhibitory potential. Additional molecular dynamics (MD) simulations over 200 ns along with MM-GPSA, PLIP, and principal component analysis of trajectories (PCAT) experiments were employed to verify the binding and inhibitory properties of T-1-PMPA . Afterward, T-1-PMPA was semisynthesized to validate the proposed design and in silico findings through several in vitro examinations., Results: DFT studies indicated T-1-PMPA 's reactivity using electrostatic potential, global reactive indices, and total density of states. Molecular docking, MD simulations, MM-GPSA, PLIP, and ED suggested the binding and inhibitory properties of T-1-PMPA against the EGFR protein. The in silico ADMET predicted T-1-PMPA 's safety and general drug-likeness. In vitro experiments demonstrated that T-1-PMPA effectively inhibited EGFR WT and EGFR 790m , with IC 50 values of 86 and 561 nM, respectively, compared to Erlotinib (31 and 456 nM). T-1-PMPA also showed significant suppression of the proliferation of HepG2 and MCF7 malignant cell lines, with IC 50 values of 3.51 and 4.13 μM, respectively. The selectivity indices against the two cancer cell lines indicated the overall safety of T-1-PMPA . Flow cytometry confirmed the apoptotic effects of T-1-PMPA by increasing the total percentage of apoptosis to 42% compared to 31, and 3% in Erlotinib-treated and control cells, respectively. The qRT-PCR analysis further supported the apoptotic effects by revealing significant increases in the levels of Casp3 and Casp9. Additionally, T-1-PMPA controlled the levels of TNFα and IL2 by 74 and 50%, comparing Erlotinib's values (84 and 74%), respectively., Conclusion: In conclusion, our study's findings suggest the potential of T-1-PMPA as a promising apoptotic anticancer lead compound targeting the EGFR., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)