Abstract LB428: Discovery of KY-001:A Direct Inhibitor of TEAD-YAP Protein-Protein Interaction for the Treatment of Advanced Solid Tumors with Abnormal Hippo Signaling Pathway
Authors: Zhao Kehao , Zhag Yong , Shi Yufang , Chen Jian 
Published: April 2024

Background:The Hippo signaling is an important pathway that plays a crucial role in the regulation of numerous biological processes. The binding of YAP/TAZ transcriptional coactivators to TEAD proteins is the core of Hippo signaling in regulating the expression of a variety of genes that mediate many cellular functions. Abnormalities of Hippo signaling including mutation deficiency, fusion and YAP/TAZ overexpression are often found in solid tumors associated with excessive proliferation, drug resistance, or tumor immune evasion. Blocking the Hippo transcription activation, particularly the TAP/TAZ and TEAD interaction, therefore is an attractive therapeutic strategy for the treatment of advanced solid tumors associated with Hippo dysregulation.

Results:We have developed a small molecule inhibitor, KY-001, that can bind to TEAD protein and directly disrupt its interaction with YAP/TAZ, thereby blocking Hippo signaling pathway. KY-001 can bind to TEAD (1-4) proteins with strong YAP/TAZ competitive activities in biochemical assays and can inhibit TEAD-YAP mediated transcriptional signals in cell. KY-001 selectively and potently inhibits the proliferation of cancer cells harboring Hippo deficient mutations, such as mesothelioma, lung cancer and other cell lines. Importantly, KY-001 directly affects the expression of some target genes downstream of YAP/TAZ-TEAD transcription activation in cell. KY-001 can strongly inhibit tumor growth in a dose dependent manner against Hippo mutation mesothelioma cancers in two different xenograft mouse tumor models. In addition, KY-001 shows remarkable synergistic effects with EGFR or KRAS G12C inhibitors in mouse non-small lung cancer models, suggesting it may be a promise therapy for treating targeted therapy induced resistant tumors with Hippo dysregulation. Pre-clinical studies shows that KY-001 has good overall druggable profiles with good safety windows in several animal species. Collectively, KY-001 shows high potency and selectivity in vitro and strong anti-tumor activities against Hippo mutation deficient cancers in pre-clinical models.

Conclusions:KY-001 is a small molecule drug candidate which directly inhibits the interactions between TEAD and YAP1/TAZ proteins, thereby blocking the transcriptional activation of downstream Hippo signaling. In various tumor models, KY-001 monotherapy shows good efficacy for Hippo

mutation deficient tumors. KY-001 also synergizes with other targeted therapy such as EGFR or KRAS G12C inhibitors for treating non-small lung cancers. KY-001 is expected to enter clinical studies in H2, 2024 for the treatment of Hippo dysregulated solid tumors.

Citation Format: Kehao Zhao, Yong Zhag, Yufang Shi, Jian Chen. Discovery of KY-001:A Direct Inhibitor of TEAD-YAP Protein-Protein Interaction for the Treatment of Advanced Solid Tumors with Abnormal Hippo Signaling Pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB428.