Abstract 1614: Antitumor activity of novel and potent YAP/TAZ-TEAD inhibitorstargeting the Hippo pathway in solid tumors
Authors: Kim Jisook , Jung Seung Hyun , Han Seon Yeong , Yoon Jihee , Kim Minjeong , Byun Jooyun , Moon Heesun , Lee Eunyoung , Kim Yu-Yon , Park Hyunjin , Jeon So-Ye , Ahn Young Gil , Kim Young Hoon , Suh Kwee Hyun 
Published: April 2023

The Hippo pathway is evolutionarily conserved and known to regulate diverse cellular processes, including cell survival, proliferation, differentiation, migration, and organ size. The key regulator of Hippo pathway is transcriptional enhanced associate domain (TEAD) transcription factors, which directly bind with YAP/TAZ and then drive the multiple signaling by activating target gene expression on nuclear. Loss-of-function mutations in the upstream activators, NF2-LATS1/2-MST1/2, trigger YAP/TAZ nuclear translocation and target gene transcription (Hippo-off state). This YAP/TAZ-TEAD complex is overexpressed and leads to metastatic progression in various cancers including malignant mesothelioma, NSCLC, ovarian cancer or cholangiocarcinoma. A recent development in targeting the Hippo pathway has been focused on the discovery of a central lipophilic pocket in TEAD amenable to the small-molecule binding site of autopalmitoylation. Within this lipophilic palmitate pocket, post-translational S-palmitoylation of TEAD at a conserved catalytic cysteine (Cys) residue (e.g., C380) leads to TEAD stabilization and is believed to be critical for maintaining appropriate protein folding to enable the formation of the transcriptionally active YAP/TAZ -TEAD complex. Therefore, targeting the palmitate pocket with allosteric small molecules inhibitor disrupt the formation of the YAP/TAZ-TEAD complex and modulate YAP/TAZ-TEAD driven gene transcription. We have identified a series of novel, potent small-molecule inhibitors of the YAP/TAZ-TEAD transcriptional complex. It showed under 20 nM of potency in the inhibition of TEAD luciferase reporter assay in MCF7-TEAD-luc cells. These TEAD inhibitors inhibited YAP/TAZ-TEAD protein-protein interaction in H226 cells harboring neurofibromin 2 (NF2) alteration. In addition, our lead compounds exhibited dose-dependent growth inhibitory effects in Hippo pathway-altered cancer cell lines and reduced the YAP/TAZ-TEAD target gene expression, CTGF, and CYR61 in H226 cells. Our lead compounds, singled out and optimized based on in vitro functional assay, displayed favorable pharmacokinetic and safety profiles. Furthermore, orally administered lead compound effectively suppressed tumor growth within tolerable doses in xenograft mice with tumors harboring NF2 alteration as a major upstream molecule of the Hippo pathway. In summary, we pointed our novel YAP/TAZ-TEAD inhibitors that showed excellent efficacy in Hippo-altered mutant cancer in vitro and in vivo xenograft models. These data best support a therapeutic option for the treatment of cancers with amplified or overexpressed YAP, TAZ, or TEAD genes. Further preclinical studies will be performed and reported soon after the establishment of a preclinical candidate.

Citation Format: Jisook Kim, Seung Hyun Jung, Seon Yeong Han, Jihee Yoon, Minjeong Kim, Jooyun Byun, Heesun Moon, Eunyoung Lee, Yu-Yon Kim, Hyunjin Park, So-Ye Jeon, Young Gil Ahn, Young Hoon Kim, Kwee Hyun Suh. Antitumor activity of novel and potent YAP/TAZ-TEAD inhibitorstargeting the Hippo pathway in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1614.