一种pan-TEAD抑制剂SIGX2649，阻断Hippo-YAP/TAZ信号通路并在临床前研究中抑制实体瘤生长

The Hippo-YAP/TAZ signaling cascade is a critical regulator of tissue homeostasis, with TEAD transcription factors (TEAD1-4) serving as essential downstream effectors. Perturbation of Hippo signaling permits YAP/TAZ nuclear accumulation, leading to TEAD-mediated transcriptional programs that drive oncogenic processes such as tumor cell proliferation, resistance to apoptosis, drug resistance, and remodeling of the tumor microenvironment. Here, we report the discovery of SIGX2649, a potent pan-TEAD inhibitor identified through AI-guided design and organoid-based screening. Leveraging generative AI and predictive AI models significantly accelerated lead identification and optimization during SIGX2649's development. SIGX2649 blocks palmitoylation of TEAD1/2/3/4, disrupts YAP/TAZ-TEAD protein interaction, and suppresses TEAD-dependent transcription. Notably, SIGX2649 displays a superior capacity to enhance the binding of the transcriptional repressor VGLL4 to TEAD relative to other multi-TEAD inhibitors, thereby further strengthening its pharmacological activity. Consequently, it inhibits proliferation across a spectrum of tumor models in vitro, including YAP-activated liver-cancer organoids and mesothelioma cells bearing LATS mutations and NF2 loss. In vivo, SIGX2649 exhibited robust antitumor efficacy in xenograft models, favorable pharmacokinetics, and minimal hepatic- or renal- targeted toxicity compared with other TEAD inhibitors under comparable efficacy. Combined with RAS-pathway inhibitors, SIGX2649 elicits pronounced synergistic responses in KRAS-mutant solid tumors. The robust efficacy and considerable safety characteristics presented by SIGX2649 in preclinical trials support its potential to serve as a highly promising small-molecule therapeutic in future cancer treatment.