Degraders of TEAD Transcription Factors Based on Interface 3 Binders

Abstract

TEAD transcription factors have emerged as clinically validated targets for Hippo-altered cancers, e.g., mesothelioma driven by NF2 inactivation/deficiency. We have developed a series of novel small molecule targeted protein degraders of TEAD, based on binders to TEAD Interface 3. In cells, the compounds induce degradation of TEAD by formation of a ternary complex with Cereblon, leading to ubiquitination of TEAD and subsequent proteasomal degradation. In a cell-based luciferase reporter assay the degraders show low nanomolar activities. The downstream effects of TEAD degradation were further investigated by qPCR analyses of bona fide YAP–TEAD target genes such as CTGF, Cyr61 and AMOTL2. The effectiveness of the TEAD degraders were compared to other classes of TEAD modulators such as palmitoylation and YAP–TEAD protein–protein interaction inhibitors by means of cellular viability and proliferation assays using various mesothelioma cell lines. Finally, we performed an unbiased, quantitative high-throughput drug combination screening1 by combining one selected TEAD degrader with a library of approximately 2,800 oncology-focused drugs.

Related file

The poster can be downloaded here.