Discovery and biological evaluation of carborane-containing derivatives as TEAD auto palmitoylation inhibitors

Abstract

Transcriptional enhanced associate domain (TEAD) proteins are key downstream effectors of the Hippo signaling pathway that play a crucial role in various cell processes including tissue development, regeneration, cell proliferation and cancer. TEADs contain a hydrophobic auto-palmitoylation pocket that can bind palmitic acid and stabilize TEADs from being degraded. Inhibitors targeting this palmitoylation pocket typically consist of hydrophobic pharmacophores. Carboranes is a cage-shaped molecule exhibiting superior hydrophobicity compared to adamantane or phenyl groups. Herein, we incorporated carborane into known TEAD inhibitors for better interaction with the hydrophobic palmitate pocket. Compounds 1f and 1l are identified as TEAD transcription inhibitors with strong anti-proliferation and anti-migration activities toward prostate cancer cell lines. They also significantly reduced TEAD-regulated downstream gene expressions.