A VERSATILE SYNTHETIC DIMERIZER FOR THE REGULATION OF PROTEIN-PROTEININTERACTIONS

The use of low molecular weight organic compounds to induce dimerizati on or oligomerization of engineered proteins has wide-ranging utility in biological research as well as in gene and cell therapies, Chemical ly induced dimerization can be used to activate intracellular signal t ransduction pathways or to control the activity of a bipartite transcr iption factor, Dimerizer systems based on the natural products cyclosp orin, FK506, rapamycin, and coumermycin have been described. However, owing to the complexity of these compounds, adjusting their binding or pharmacological properties by chemical modification is difficult. We have investigated several families of readily prepared, totally synthe tic, cell-permeable dimerizers composed of ligands for human FKBP12. T hese molecules have significantly reduced complexity and greater adapt ability than natural product dimers, We report here the efficacies of several of these new synthetic compounds In regulating two types of pr otein dimerization events inside engineered cells-induction of apoptos is through dimerization of engineered Fas proteins and regulation of t ranscription through dimerization of transcription factor fusion prote ins, One dimerizer in particular, AP1510, proved to be exceptionally p otent and versatile in all experimental contexts tested.