Phase separation-based HTS identifies cobimetinib as a YAP-TEAD inhibitor that suppresses hyperactivated YAP-induced cancer progression.

Abstract

The Hippo signaling pathway prevents unchecked cell growth, coordinates apoptosis, and preserves proper organ function. Dysregulation of this pathway has been implicated in a myriad of diseases, particularly in cancer. The YAP (Yes-associated protein)-TEAD (TEA domain transcription factor) complex, the key transcriptional downstream effector of the Hippo pathway, hence stands out as an appealing target for therapeutic intervention. In this study, we developed a high-throughput screening (HTS) assay leveraging phase separation principles and found that the US Food and Drug Administration-approved clinical drug cobimetinib is a potent inhibitor of the YAP-TEAD complex. Cocrystallization studies of cobimetinib with TEAD showed that cobimetinib bound to the TEAD lipid pocket and disrupted TEAD palmitoylation. Cobimetinib could overcome resistance to mitogen-activated protein kinase kinase 1/2 inhibitors and to the first-line drug sorafenib in vivo. In addition, cobimetinib suppressed tumor growth and tumorigenesis associated with hyperactivated YAP-TEAD activities in a mouse model of lung cancer. Furthermore, it bolstered the efficacy of the first-line drugs sorafenib and lenvatinib in inhibiting both hepatocellular carcinoma tumor growth and tumorigenesis. These findings establish a strategy for identifying and refining inhibitors of the YAP-TEAD complex in the treatment of cancers driven by aberrant YAP-TEAD activity.