Signet Therapeutics Announces Early FDA IND Clearance for SIGX2649, a First-in-Class Pan-TEAD Inhibitor Targeting the Hippo Pathway

SIGNET announced today that its independently developed potential First-in-class/Best-in-class innovative targeted drug, SIGX2649, has received the FDA's New Drug Clinical Trial (IND) approval ahead of schedule, fully demonstrating the clinical urgency of the TEAD inhibitor pipeline.

This is the second innovative drug pipeline of Signet Therapeutics to enter clinical trials, following the world's first targeted drug for diffuse gastric cancer, SIGX1094, entering Phase I clinical trials. It also represents another milestone achievement of the "AI + organoid" joint R&D model by Signet Therapeutics and XtalPi (2228.HK), marking the company’s targeted drug pipeline matrix for solid tumors gradually moving into the clinical stage.

Overcoming "Undruggable" Targets, SIGX2649 Features a Unique Mechanism

The Hippo signaling pathway, comparable to major tumor-driving pathways like P53, Myc, and RAS, has long been considered an undruggable target. SIGX2649 is a pan-TEAD (TEAD 1-4) inhibitor that blocks the Hippo-YAP/TAZ signaling pathway by targeting TEAD, the binding protein of YAP (an undruggable core transcription factor in the Hippo pathway), thereby inhibiting the proliferation, metastasis, and drug resistance of solid tumors.

This drug has a dual mechanism of action, not only inhibiting TEAD palmitoylation to prevent the binding of YAP and TEAD, but also simultaneously enhancing the binding of VGLL4 and TEAD, further strengthening the inhibition of YAP/TEAD function. Preclinical studies show that SIGX2649 exhibits excellent anti-proliferative activity in various in vitro tumor models (including liver cancer organoids, mesothelioma, etc.), with significant in vivo tumor suppression effects, good pharmacokinetics, and lower renal-targeted toxicity compared to similar drugs under development. It holds great therapeutic potential for unmet clinical needs in advanced solid tumors such as small cell lung cancer, mesothelioma, and liver cancer. Additionally, when combined with RAS pathway inhibitors, it demonstrates significant synergy in KRAS-mutant solid tumors like non-small cell lung cancer and colorectal cancer.

No similar drugs have been marketed globally, and SIGX2649 is expected to become a First-in-class drug.

Currently, there are no TEAD inhibitors approved for marketing globally, with the fastest TEAD inhibitor only in Phase I clinical trials. SIGX2649 can precisely cover all four subtypes of the TEAD family and is the first Pan-TEAD inhibitor, achieving optimal preclinical efficacy and is expected to become the world's first marketed Pan-TEAD inhibitor.

Its core preclinical research data has been selected for the 2026 American Association for Cancer Research (AACR) Annual Meeting report, making its global debut at the world's top oncology academic conference, showcasing its differentiated mechanism and advantages in clinical translation.

"AI + Organoid" Platform Further Validated, Solid Tumor Treatment Matrix Accelerates Formation

SIGX2649, developed based on SIGNET's world-first "Organoid+AI" platform, has once again demonstrated the efficiency and replicability of this collaborative R&D model with its rapid IND approval. In the future, Signet Therapeutics will continue to build a multi-indication pipeline matrix for solid tumors and non-cancer indications, bringing more innovative therapies to patients worldwide.

SIGNET is a pioneer in the global "organoid + AI"-powered innovative targeted drug R&D model, as well as a national high-tech enterprise and a specialized and innovative enterprise. The company's founding team consists of outstanding talents from top institutions such as Harvard University, MIT, and the Chinese Academy of Sciences. As first/corresponding authors, they have published more than 20 groundbreaking research papers on gastric cancer, esophageal cancer, and other tumors in journals with impact factors exceeding 20, including Nature, Nature Medicine, and Cancer Cell, establishing itself as a global leader in gastric and esophageal cancer research. Since its establishment in Shenzhen at the end of 2020, the company has completed nearly 300 million yuan in financing and project funding, and holds more than 40 core intellectual properties.

The company currently has multiple First-in-class drug pipelines and an organoid service platform. Its core pipeline, SIGX1094, is the world's first targeted drug for diffuse gastric cancer. It has successively obtained IND approval from the U.S. FDA and China NMPA, and received Orphan Drug Designation (ODD) and Fast Track Designation (FTD) from the U.S. FDA. In August 2025, this drug was nominated for the Galien Award, known as the "Nobel Prize of the pharmaceutical industry." It is currently undergoing Phase I clinical trials at the Peking University Cancer Hospital and will soon enter Phase II clinical trials. This pipeline is also the world’s first drug to be advanced to the clinical stage via an "organoid + AI" technology platform. The second drug pipeline, SIGX2649, is a pan-TEAD inhibitor targeting the key downstream effector of the Hippo signaling pathway. There are currently no marketed drugs for this target, and it has already received IND approval from the U.S. FDA. The organoid service platform not only supports its own drug pipelines but also actively empowers large pharmaceutical companies in new drug development. Collaborative institutions include Shenzhen Second People's Hospital, the University of Hong Kong, the Hong Kong University of Science and Technology, Shenzhen BioRay Pharma, and Zhen Biosciences, helping to bring more innovative drugs to life.

Since its establishment at the end of 2020, Signet Therapeutics' forward-looking strategic layout of an "Organoid+AI"-powered technology system for innovative targeted cancer drug development has gained international authoritative recognition. It was featured on the homepage of Fierce Biotech, a globally renowned biotech media outlet, and hailed as the "NEXT Generation" paradigm in cancer drug development. In April 2025, the U.S. FDA officially issued a statement explicitly supporting the gradual replacement of traditional animal testing with organoid and AI technologies, fully validating the foresight and scientific rigor of the company’s technical layout from four years prior.