<p>Protein kinases play a pivotal role in various cellular processes, and their dysregulation is often associated with cancer. In this study, we present a detailed computational investigation of OxyICI (oxyisocyclointegrin) as a potential multi target inhibitors of key protein kinases involved in tumorigenesis, validating its scaffold against well-known inhibitors (IPA-3, Alisertib, Ibrutinib and Afatinib). Molecular docking simulations showed that OxyICI exhibits binding affinities comparable to or exceeding those of standard inhibitors to four key targets: PAK1 (−8.9 kcal/mol <i>vs.</i> IPA-3's −8.3 kcal/mol), Aurora-A (−8.6 kcal/mol <i>vs.</i> Alisertib's −8.1 kcal/mol), BTK (−8.5 kcal/mol <i>vs.</i> Ibrutinib's −8.5 kcal/mol), and most notably, EGFR (−9.4 kcal/mol <i>vs.</i> Afatinib's −8.6 kcal/mol).These robust interactions involve distinct binding mechanisms, with OxyICI primarily utilizing a network of conventional hydrogen bonds with critical active site residues. Pharmacokinetic predictions confirmed that OxyICI adheres to drug-likeness criteria, predicting favourable oral bioavailability and high gastrointestinal absorption potential, while being minimally permeant to the blood-brain barrier. <i>In silico</i> toxicity analysis predicted a manageable acute toxicity profile (LD₅₀ =566 mg/kg). DFT calculations at the B3LYP/DEF2-TZVP level revealed a moderate HOMO-LUMO gap, indicating a balanced reactivity profile. The consistently strong and often superior predicted binding affinities of the OxyICI scaffold, coupled with its favourable pharmacokinetic and toxicity profiles, strongly warrant further exploration to be used it as a future kinase inhibitor.</p> Graphical abstract <p>Oxyisocyclointegrin exhibits strong potential as a protein kinase inhibitor. The scaffold's robust binding affinities with key protein kinases such as PAK-1, Aurora-A, BTK and EGFR are demonstrated through advanced molecular docking studies, pharmacokinetic evaluation and DFT calculations.</p> <p></p>