Many common disease-causing mutations result in loss-of-function (LOF) of the proteins in which they occur. LOF mutations have proven recalcitrant to pharmacologic intervention, presenting a challenge for the development of targeted therapeutics. Polycomb repressive complex 2 (PRC2), which contains core subunits (EZH2, EED, and SUZ12), regulates gene activity by trimethylation of histone 3 lysine 27. The dysregulation of PRC2 catalytic activity by mutations has been implicated in cancer and other diseases. Among the mutations that cause PRC2 malfunction, an I363M LOF mutation of EED has been identified in myeloid disorders, where it prevents allosteric activation of EZH2 catalysis. We describe structure-based design and computational simulations of ligands created to ameliorate this LOF. Notably, these compounds selectively stimulate the catalytic activity of PRC2-EED-I363M over wildtype-PRC2. Overall, this work demonstrates the feasibility of developing targeted therapeutics for PRC2-EED-I363M that act as allosteric agonists, potentially correcting this LOF mutant phenotype.