Transcription factors (TFs) are critical cancer drivers making them compelling targets for small molecule inhibition. The use of chemical proteomics to screen covalent small molecule libraries in live cells has enabled the identification of compounds that bind in previously unrecognized pockets on TFs. Creative approaches to developing biophysical and functional assays can overcome the challenges of working with recombinant TF proteins and provide a path toward drugging these important targets.

Activity of the YAP/TAZ-TEAD complex represents a compelling pharmacologic target. We have identified novel small molecules that bind to the TEAD auto-palmitoylation pocket and these compounds are highly potent, orally bioavailable, and active against multiple cancer cell lines. In vivo models of Hippo pathway-altered xenografts showed that our inhibitors deliver consistent monotherapy activity, with dose-dependent and durable tumor regressions achieved at well-tolerated doses.

The transcription factor IKZF2 is required for maintaining stable Tregs. Depletion of IKZF2 converts Tregs into effector-T cells and loss of suppressive activity. Protein degradation enables targeting undruggable proteins without known ligand binding-sites (i.e. IKZF2). PLX-4107 was designed to induce a novel interaction between IKZF2 and the E3 Cereblon promoting protein degradation. PLX-4107 selectively degrades IKZF2 resulting in Treg conversion into effector-like T cells, antitumor activity and enhanced immune checkpoint therapy efficacy.