Low-molecular-weight compounds that disrupt protein protein interactions (PPIs) have tremendous potential applications as clinical agents and as chemical probes for investigating intracellular PPI networks. However, disrupting PPIs is extremely difficult due to the large, flat interfaces of many proteins, which often lack structurally defined cavities to which drug-like molecules could bind in a thermodynamically favorable manner. Here, we describe a series of bivalent compounds that anchor to the enzyme active site to deliver a minimally sized surface-binding module to the targeted surface involved in transient PPI with a substrate. These compounds are capable of significantly inhibiting enzymatic reactions involving protein surface substrate interaction in the single-digit nanomole range. Inhibitors of farnesyltransferase (FTase), which possesses a negatively charged local area on its a-subunit, were designed by attaching a module derived from a branched monoamine-containing gallate to a conventional active-site-directed CVIM tetrapeptide using an alkyl spacer. A significant improvement in inhibitory activity (>200-fold) against farnesylation of the K-Ras4B peptide was observed when the gallate module was attached to the CVIM tetrapeptide. Furthermore, the bivalent compounds had submicromolar inhibitory activity against geranylgeranylation of the K-Ras4B peptide catalyzed by GGTase I, which has an a-subunit identical to that of FTase. The anchoring strategy we describe would be useful for designing a new class of PPI inhibitors as well as dual enzyme inhibitors targeting common surface structures.