Signet Therapeutics Submits IND Application to FDA for SIGX2649, a First-in-Class Pan-TEAD Inhibitor Targeting the Undruggable Hippo Pathway

Today, Signet Therapeutics' independently developed potential First-in-class/Best-in-class innovative targeted drug SIGX2649 for the Hippo pathway has completed all preclinical studies and an Investigational New Drug (IND) application has been officially submitted to the U.S. Food and Drug Administration (FDA). The Hippo pathway, along with pathways such as P53, Myc, and RAS, was previously considered an undruggable target among mainstream tumor drivers. SIGX2649 is a pan-TEAD (Tead 1-4) inhibitor that blocks the Hippo-YAP/TAZ signaling pathway by targeting TEAD, the binding protein of the core transcription factor YAP (an undruggable target) in the Hippo pathway, thereby inhibiting the proliferation, metastasis, and drug resistance of solid tumors, overcoming the challenge of undruggability in the Hippo pathway. Its core preclinical research data has been selected for presentation at the 2026 American Association for Cancer Research (AACR) Annual Meeting, marking its debut on the global top oncology academic stage and showcasing its differentiated mechanism and clinical translational potential.

This is another milestone achievement for SIGNET and XtalPi (2228.HK) in their "AI + Organoid" joint R&D model, following the entry of SIGX1094, the world’s first targeted drug for diffuse gastric cancer, into Phase I clinical trials. It marks the comprehensive advancement of the company’s solid tumor targeted drug pipeline portfolio into the clinical stage, further validating the efficiency and replicability of the "AI + Organoid" joint R&D model. This provides ongoing momentum for SIGNET to build a multi-pipeline, multi-indication solid tumor treatment matrix.

SIGX2649, developed based on SIGNET's world-first "Organoid+AI" platform, targets the core TEAD of the Hippo-YAP/TAZ pathway. Through a dual mechanism (inhibiting TEAD palmitoylation and enhancing VGLL4 binding to TEAD), it blocks tumor proliferation, metastasis, and drug resistance, offering unique differentiation advantages. Currently, there are no TEAD inhibitors on the market globally, with the fastest competing candidates only in Phase I trials; SIGX2649 precisely covers all four TEAD subtypes, balancing efficacy and safety, with the potential to become a First-in-class/Best-in-class drug.

SIGX2649 Demonstrates Robust Preclinical Data Validation: Exhibits Excellent Anti-Proliferative Activity in Multiple In Vitro Tumor Models (Including Liver Cancer Organoids, Mesothelioma), Strong Tumor Suppression in In Vivo Models, and Favorable Pharmacokinetics. Compared to Similar Drugs Under Research, It Shows Lower Renal-Targeted Toxicity and Significant Synergistic Effects When Combined with RAS Pathway Inhibitors in KRAS-Mutant Solid Tumors. Core Data Related to This Was Presented at the 2026 AACR Annual Meeting.

Signet Therapeutics is a pioneer in the global "organoid + AI"-powered innovative targeted drug R&D model, and is a national high-tech enterprise as well as a specialized and new 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 stomach cancer, esophageal cancer, and other cancer fields in journals with an impact factor of over 20, such as Nature, Nature Medicine, and Cancer Cell, making them a global leader in stomach 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 four First-in-class drug pipelines and one organoid platform under development. The core pipeline, SIGX1094, is the world’s first targeted drug for diffuse gastric cancer. It has obtained IND approval from both the U.S. FDA and China NMPA, as well as 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." Currently, it is undergoing Phase I clinical trials at the Peking University Cancer Hospital. This pipeline is also the world’s first drug to be advanced into clinical trials through 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 an IND application will soon be filed simultaneously in the U.S. and China.

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