SIGX2649

SIGX2649 is a potent, small-molecule pan-TEAD inhibitor developed by Signet Therapeutics using generative AI and organoid-based screening platforms. It targets the Hippo-YAP/TAZ signaling pathway by binding to the palmitoylation pocket of TEAD transcription factors (TEAD1, TEAD2, TEAD3, and TEAD4), thereby blocking their auto-palmitoylation and disrupting the interaction with oncogenic co-activators YAP and TAZ. A distinguishing feature of SIGX2649 is its superior capacity to enhance the binding of the transcriptional repressor VGLL4 to TEAD compared to other multi-TEAD inhibitors, which further suppresses TEAD-dependent transcriptional programs. Preclinical studies have demonstrated robust antitumor efficacy in various models, including YAP-activated liver cancer organoids and mesothelioma cells with NF2 loss or LATS mutations. Additionally, SIGX2649 shows synergistic potential when combined with RAS-pathway inhibitors in KRAS-mutant solid tumors and exhibits a favorable safety profile with minimal renal and hepatic toxicity.