Abstract: Within the chemical space of protein-protein interactions (PPIs), transient, modest affinity PPIs play a central role in a variety of cellular functions, including protein folding and transcription. Dysregulation of this class of PPIs is at the heart of diseases ranging from cancer to neurodegenerative disorders. For example, in several types of AML, leukemogenesis is dependent upon the loss of one transcriptional activator-coactivator interaction (MLL-p300) and the maintenance or amplification of a second (cMyb-p300). Despite their importance and their prevalence, such transient and modest affinity PPIs are often classified as ‘undruggable’, with few successful strategies for small molecule modulator discovery. A significant challenge has been that the binding partners often have significant disorder and are thus difficult to characterize structurally alone or in complex. A strategy for the identification of chemical co-chaperones that capture particular conformations of transcriptional coactivators and in doing so selectively modulate the assembly of transcriptional activator-coactivator complexes in vitro and in cells will be described.