Recent advances in TEAD modulators: A medicinal chemistry perspective

Transcriptional enhancer associate domain (TEAD) transcription factors serve as the essential DNA-binding effectors that transduce Hippo pathway signaling into transcriptional programs. In mammals, the four TEAD homologues (TEAD1-4) primarily function through association with the transcriptional coactivators YAP and TAZ. Hyperactivation of the YAP/TAZ-TEAD axis confers hyperproliferative, pro-survival, and migratory phenotypes, a hallmark of numerous solid malignancies, including gastric, colorectal, breast, prostate, and mesothelioma cancers. Consequently, TEAD represents a compelling yet pharmacologically challenging target for anticancer intervention. Contemporary TEAD modulators have evolved into three principal modalities: inhibitors disrupting the YAP/TAZ-TEAD protein-protein interaction (PPI), ligands occupying the conserved TEAD palmitoylation pocket, and proteolysis-targeting chimeras (PROTACs) mediating TEAD degradation. This review provides a comprehensive overview of TEAD modulators disclosed since 2021, emphasizing the underlying medicinal chemistry strategies. Beyond mere enumeration of bioactive scaffolds, we trace the evolution of representative hits into optimized leads and clinical candidates, delineate how novel chemotypes alter binding conformations in crystallographic and docking studies, and correlate these structural modifications with biochemical, cellular, and in vivo efficacy. Furthermore, we critically assess the current clinical landscape, address persistent challenges regarding safety and selectivity, and outline emerging technological opportunities in TEAD-directed drug discovery.