Protein tyrosine phosphatases (PTPs), including PTP1B, have been implicated in the dephosphorylation and inactivation of epidermal growth factor receptor (EGFR). Hence, enhanced PTP1B-mediated EGFR dephosphorylation could serve as a strategy to suppress oncogenic EGFR signalling in cancers such as mammary, non-small cell lung and ovarian carcinomas and in head and neck and colon tumours. A combination of computational and biological approaches were taken to discover small molecules which potentially promote and tether the protein-protein interaction between PTP1B and EGFR. Briefly, binding between crystal structures of PTP1B and EGFR proteins were simulated by pairwise, Fast Fourier Transform-based rigid docking and analysed for stability using Monte Carlo minimizations. Two crystal structures of PTP1B in complex with a cytoplasmic EGFR fragment (residues DADEYL, positions 988-993) were identified to guide selection of most “native” protein-protein complex. Druggable chemical pockets created at the interface of the selected PTP1B-EGFR complex were determined, and subsequently used as our target for structure-based virtual screening of selected compound databases. As proof of concept, immunoassays to investigate their ability to inhibit EGFR tyrosine in EGFR overexpressing A431 cells and its effects on downstream substrates such as Mek/Erk and Akt, are currently underway. It is duly noted that current trends in PTP1B research in the context of type 2 diabetes pertains to its inhibition as a means to antagonise insulin receptor signalling and thereby enhancing insulin response and alleviating insulin resistance. Here, we rather aim to not agonise PTP1B activity, but target it specifically to aberrantly activated EGFR. The impact of potentially sequestering PTP1B to EGFR in vivo for insulin sensitivity and obesity resistance is discussed.