The Hippo signaling pathway is critical for regulating cell growth, tissue homeostasis, and organ size. Dysregulation of this pathway has been associated with a range of pathologies, especially cancer, through its modulation of downstream effectors-Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ). These proteins bind to transcriptional enhanced associate domain (TEAD) proteins and function as transcription factors in the nucleus, producing oncogenic target genes such as CTGF and CYR61. TEAD proteins require palmitoylation via a covalent bond with cysteine in the central pocket to bind YAP/TAZ. Therefore, competitive inhibition that prevents palmitoylation could serve as an effective anticancer strategy. In this study, we analyzed the crystal structures of the known inhibitor VT-105 bound to TEAD3 to identify new binding spots that were previously unexplored, with the aim of discovering more potent compounds using structure-based drug design. Consequently, we identified a novel hydrogen-bonding site and discovered C-2, which effectively binds to this site, as confirmed by X-ray crystallography. Furthermore, C-2 exhibited stable pharmacokinetic properties and demonstrated impressive efficacy in a mouse xenograft model.