AI and Organoid-Driven Innovation: XtalPi-Backed Signet Therapeutics Advances First-in-Class Pan-TEAD Inhibitor SIGX2649 into IND-Enabling Stage

Jan 16, 2026 08:53 CST Updated 08:53

XtalPi

Computation-Driven Innovative Drug R&D Provider

SIGNET

Innovative Targeted Cancer Drug Developer

Recently, XtalPi (2228.HK) Incubated company Signet Therapeutics announced the second innovative drug pipeline discovered in collaboration with XtalPi.SIGX2649 has completed preclinical studies, about toChina, U.S. Regulatory Authorities Simultaneously Submit New Drug Clinical Trial (IND) Applications; Relevant Data to Debut at the 2026 American Association for Cancer Research Annual Meeting（AACR Annual Meeting）。SIGX2649 is a potential first-in-class or best-in-class pan-TEAD inhibitor with a broad drug market in the field of solid tumor treatment.Following the entry of SIGX1094, the world’s first targeted drug for diffuse gastric cancer, into Phase I clinical trials, this marks the second innovative drug pipeline from XtalPi and SIGNET to initiate clinical application. In the future, XtalPi will...Entitled to receive a significant proportion of the commercialization revenue of the pipeline, with a maximum of double-digit percentage.The consecutive achievement of milestones in two pipelines fully demonstrates XtalPi's ongoing R&D breakthrough capabilities in producing pipeline assets, further confirming the clinical translation efficiency of the "AI + organoid" R&D paradigm.

TEAD Inhibitors as Core Targets of the Hippo Pathway Show Promising Prospects in the Treatment of Solid Tumors Such as Mesothelioma, Liver Cancer, and Lung CancerIts research and development has become a new hotspot in the field of cancer treatment in recent years.Solid tumors account for approximately 90% of all tumor incidences, with a global market size reaching $226.97 billion in 2024, and it is projected to exceed $532.48 billion by 2032. However, the TEAD protein family consists of four subtypes with varying functions and expression patterns. Their inhibitors must strike a balance between potent inhibition and safety. Currently, there are no approved drugs globally, and the most advanced...TEAD InhibitorsIn Phase I clinical stage.

SIGX2649 is a pan-TEAD inhibitor co-developed by XtalPi and Signet Therapeutics based on the "AI + organoid" collaboration.Preclinical data show that SIGX2649 can effectively inhibit all four TEAD subtypes and promote the binding of the transcriptional repressor VGLL4 to TEAD, achieving "dual blockade." Based on this differentiated mechanism,SIGX2649 has stronger anti-tumor activity compared to other TEAD inhibitors, with significantly lower kidney-targeted toxicity:In a variety of in vitro tumor models,SIGX2649All showed excellent anti-proliferative activity;In in vivo models, it demonstrated potent anti-tumor efficacy and favorable pharmacokinetic properties. These advantages makeSIGX2649 is expected to become a first-in-class/best-in-class targeted drug in the Hippo pathway field and has the opportunity to gain support from priority review policies through the development of rare tumor indications, thereby accelerating the completion of clinical trials.Bring new treatment hope to patients with specific solid tumors who have significant unmet clinical needs. In addition, when used in combination with RAS pathway inhibitors, SIGX2649 has triggered significant synergistic effects in KRAS-mutant solid tumors, demonstrating broader potential for drug combinations.

In the drug discovery of SIGX2649, XtalPi, relying on its AI + robotics intelligent drug discovery platform, collaborates with SIGNET's organoid model technology to efficiently integrate rational drug design with efficacy evaluation that is closer to the human body’s real environment, laying a core foundation for identifying drug molecules with superior activity, novel structures, and higher clinical success rates.

During the project, XtalPi first generated a library of millions of active molecules targeting the TEAD protein through its AI platform. Using high-precision computational chemistry tools, XtalPi performed multi-dimensional computational evaluations on key properties such as molecular activity, subtype selectivity, structural novelty, and synthetic feasibility, rapidly refining the drug-like molecule library from millions to hundreds. Based on this, combined with SIGNET's organoid models for efficient screening, XtalPi successfully obtained several lead compounds with excellent activity against different subtypes and novel molecular scaffolds. Through multiple rounds of ADMET property evaluations and iterative optimization combining physical models and AI models, XtalPi constructed a candidate molecule library with both activity and drug-likeness, as well as diverse subtype selectivity. Finally, after systematic in vivo pharmacodynamics and safety validation, the pan-TEAD inhibitor SIGX2649 was identified as the preclinical candidate compound (PCC).

Previously, the first pipeline SIGX1094, a collaboration between XtalPi and Signet Therapeutics, has been nominated for the "Nobel Prize in Medicine," the Prix Galien, and entered Phase I clinical trials due to its breakthrough potential. As a global leading AI drug discovery engine, XtalPi continuously validates the clinical translation and commercialization capabilities of its AI + robotics drug discovery platform through successive successes in co-developed pipelines such as SIGX1094 and SIGX2649.In the future, the company will further leverage its proven platform advantages, actively participate in the global R&D process of innovative drugs, and drive more high-potential pipeline innovations.Accelerate the development of innovative drugs with market potential and differentiated competitiveness for partners,Continuously create value for all parties in the industry.

● CloseYuSIGNET●

SIGNET is a pioneer in the global "organoid + AI" drug research and development model. It is a specialized and innovative enterprise in Shenzhen and has been recognized as a national high-tech enterprise. The company was initially founded on the campus of Harvard University and officially established in Shenzhen by the end of 2020. To date, it has completed nearly 300 million yuan in financing and project funding. The company currently has four drug pipelines. The first pipeline is developing SIGX1094, the world's first targeted drug for diffuse gastric cancer, which has received IND approval from both the U.S. FDA and China's NMPA. It has also obtained Orphan Drug Designation and Fast Track Designation from the U.S. FDA, and has entered Phase I clinical trials.

SIGNET is not only the phonetic translation of Signet but also adheres to the vision of "Full of Hope, Investigating Things to Attain Knowledge." The company leverages the critical role of organoid disease models that closely resemble patients' genomic characteristics in drug efficacy evaluation and novel target discovery. Combined with AI-powered screening, synthesis, and optimization of small-molecule compounds, SIGNET develops first-in-class innovative targeted drugs. In April 2025, the U.S. FDA officially issued a statement explicitly supporting the gradual replacement of traditional animal testing with organoids and AI technologies, fully validating the forward-thinking and scientific nature of its technological layout.