PLM-103

PLM-103 is a novel, orally available small-molecule inhibitor that targets the Hippo-YAP pathway through a dual mechanism. Developed by PeLeMed, it potently inhibits the YES1 kinase (a Src family kinase and upstream activator of YAP) while concurrently suppressing TEAD-mediated transcription. This dual action leads to robust inactivation of YAP signaling, which is a key regulator of tumor progression, metastasis, and immune evasion. Unlike traditional TEAD inhibitors that are often limited to mesothelioma, PLM-103 has demonstrated broad-spectrum antitumor activity in preclinical models of esophageal squamous cell carcinoma (ESCC), renal cell carcinoma (RCC), and pancreatic ductal adenocarcinoma (PDAC). Additionally, it shows synergistic potential when combined with immune checkpoint inhibitors like anti-PD-1 antibodies by enhancing CD8+ T cell infiltration and reducing regulatory T cells in the tumor microenvironment.