Abstract Because of the Hippo pathway’s unique ability to restrict TAZ/YAP-TEAD in promoting regeneration, any abnormality of its core components, may promote the migration, invasion, and malignancy of cancer cells. Aberrant overexpression of YAP/TAZ-TEAD promotes tumorigenesis and is therefore considered oncogenes in many solid tumors. Drug resistance is a major factor undermining the efficacy of cancer drugs. As YAP/TAZ-TEAD complex plays a role in intrinsic and acquired resistance to various chemotherapeutic and targeted therapy drugs, there is increasing interest in combining a TEAD inhibitor with various cancer therapies. Since elevated YAP/TAZ-TEAD activity has been implicated in multiple cancer types at various stages of cancer progression and cancer types, Drugging the TEAD hydrophobic pocket, which was discovered in 2015, remains as an attractive and proven strategy to modulate the activity. Despite the progresses, only 3 small molecule TEAD inhibitors are currently being tested in Phase I clinical trials which includes: VT3989b NCT04665206 from Vivacare, IK-930b NCT05228015 from Ikena Oncology and IAG-933, NCT0485737 from the Novartis Oncology. As such, there is a need to uncover alternative TEAD inhibitors for cancer therapeutics. We report novel small molecule inhibitors that form a covalent complex with the conserved cysteine of the TEAD palmitoylation site. Compounds inhibited TEAD transcriptional target genes in cancer cells. Cellular proliferation and colony forming assay data strongly displayed cellular sensitivity in Hippo signaling altered cancer cell lines. TEAD1 dependency of gastric cancer cell lines enhance cellular sensitivity in response to small molecule inhibitors. Transcriptional profiling and RNA seq data indicate that the covalent inhibitors specifically downregulate down-stream transcriptional target genes. With our exciting key data, we are exploring multiple other oncology targets to use our Pan-TEAD inhibitors either as a monotherapy or combination therapy. We expect to complete our Technology Disclosure on additional targets before the meeting and to add exciting data for the Cancer drug development community. Citation Format: Ramesh Kumar, Joel Toh, Joanne Thian, Noorul Farzana Mohideen, Jialin Sun, Sayan Chakraborty, Jayantha Gunaratne, Wanjin Hong. Identification of small molecule Pan-TEAD inhibitors disrupting YAP-TEAD protein-protein interaction and targeting gastric cancer cells [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 LB033.