XTAL Tech and Signet Therapeutics Achieve IND Approval for Potent pan-TEAD Inhibitor SIGX2649, Validating the AI + Organoid Drug Discovery Platform

Recently, XtalPi (2228.HK) and its incubated company, Signet Therapeutics, have once again reached a collaborative milestone, with the jointly discoveredPan-TEAD Inhibitor SIGX2649 Receives Early FDA Approval for Investigational New Drug (IND) Application, with Phase I clinical trials planned to commence as early as the third quarter of this year. SIGX2649 is the first highly potent pan-TEAD inhibitor that comprehensively targets all four subtypes of the TEAD family, and it is poised to become the first globally marketed pan-TEAD inhibitor targeting the Hippo pathway, holding broad market potential in the field of solid tumor therapy. Following the approval of SIGX1094, the world’s first targeted therapy for diffuse gastric cancer, into clinical trials, XtalPi and SIGNET have secured early approval for their second innovative pipeline.Marking the continuous clinical validation of the “AI + organoid” drug development strategy, with successful models being replicated。

The early approval of the IND application for SIGX2649 fully demonstrates the urgent clinical need for this pipeline. Its core preclinical data exhibit excellent druggability, safety, and differentiated clinical value. Meanwhile, Professor Wu Yilong, Chief Expert at Guangdong Provincial People’s Hospital and a leading figure in precision lung cancer therapy in China, will officially serve as the Leading Principal Investigator (PI) for the Phase I clinical trial of SIGX2649 and the Phase I/II clinical trial of SIGX1094 in combination with a KRAS-G12C inhibitor, thereby accelerating the global development of these two core pipelines.

The continued success of multiple investigational pipelines from XtalPi and SIGNET has strongly validated the rapid translational capability of their underlying R&D platform, “from algorithm to clinic,” as well as the significant potential of the “AI + organoid” model in tackling the development of high-value, innovative target drugs. According to the agreement between the two parties, XtalPi is entitled to receive up to a double-digit percentage of SIGX2649’sCommercialization RevenueRevenue sharing.

TEAD proteins are core nodes of the Hippo signaling pathway, which is recognized as a central oncogenic driver pathway alongside P53 and RAS.Holds broad promise in the treatment of solid tumors, including mesothelioma, liver cancer, and lung cancer, but there has long been a lack of effective drugs. The TEAD protein family comprises four subtypes with distinct functions and expression patterns, making it highly challenging to develop inhibitors that balance potent suppression of all subtypes with safety.Currently, no TEAD inhibitors have been approved for market launch worldwide., with the fastest-developing product in its pipeline also in Phase I clinical trials.

SIGX2649 is a collaboration between XtalPi and SIGNET based on “AI + Organoids” SIGX2649, a pan-TEAD (TEAD1–4) inhibitor developed through collaborative R&D, simultaneously targets all four TEAD family subtypes and demonstrates broad clinical development potential. Its dual mechanism of action— inhibiting TEAD palmitoylation while enhancing VGLL4 binding to TEAD—further amplifies the drug’s suppression of YAP/TEAD function. Preclinical studies have shown that SIGX2649 exhibits superior anti-proliferative activity in various in vitro tumor models (including liver cancer organoids and mesothelioma), significant in vivo antitumor efficacy, and favorable pharmacokinetics.Moreover, it exhibits lower renal-targeted toxicity than comparable drugs under development, offering differentiated clinical advantages and best-in-class therapeutic potential.。

SIGX2649 holds significant therapeutic potential in advanced solid tumors with substantial unmet clinical needs, such as small cell lung cancer, mesothelioma, and liver cancer. Furthermore, it demonstrates marked synergistic effects when combined with RAS pathway inhibitors in KRAS-mutant solid tumors, including non-small cell lung cancer and colorectal cancer. Based on these compelling data, the core preclinical studies of SIGX2649 have been selected for presentation at the 2026 Annual Meeting of the American Association for Cancer Research (AACR), the world’s most authoritative and influential academic conference on cancer research.

During the discovery of SIGX2649, XtalPi leveraged its quantum physics, AI, and automated synthesis platform to achieve a rapid closed-loop integration of virtual screening and physical synthesis. XtalPi first generated a library of millions of molecules using AI and employed computational chemistry to conduct multidimensional assessments of key properties, including potency, subtype selectivity, structural novelty, and synthesizability, thereby rapidly narrowing the library down to hundreds of candidates. Subsequently, robot-driven large-scale chemical synthesis and testing were utilized to efficiently complete the “Design-Make-Test-Analyze” (DMTA) closed-loop validation. Building on this foundation, XtalPi combined SIGNET’s organoid model screening to identify novel-scaffold lead compounds. These leads underwent iterative ADMET optimization through a combination of physical models and AI, and were ultimately validated for in vivo efficacy and safety, establishing SIGX2649 as a preclinical candidate (PCC).

Previously, SIGX1094, the world’s first “AI + organoid” novel drug co-developed by XtalPi and SIGNET, as well as the first FAK/SRC dual-target inhibitor to enter clinical development, has been granted Orphan Drug Designation and Fast Track Designation by the U.S. FDA and received a nomination for the 2025 Prix Galien USA. It is currently undergoing Phase I clinical trials for diffuse gastric cancer at Peking University Cancer Hospital, with Phase II trials imminent. The pace and quality of this molecule’s progression from discovery to IND submission provided direct experience replication and platform validation that facilitated the rapid approval of SIGX2649.Two molecules have successively entered clinical trials under the “AI + organoid” R&D model, with the second pipeline receiving accelerated approval., further confirming that the “AI + organoid” platform collaboration model between XtalPi and SIGNET possesses reproducible and scalable technical advantages in molecular generation, selectivity optimization, and druggability assessment.

will serve as the Principal Investigator for the Phase I clinical trial of SIGX2649 and the Phase I/II clinical trial of SIGX1094 in combination with a KRAS-G12C inhibitorProf. Wu YilongNot only is he a Chief Expert at Guangdong Provincial People's Hospital, but he is also a recipient of the IASLC Distinguished Scientist Award from the International Association for the Study of Lung Cancer (IASLC). With nearly 40 years of experience in research on precision therapy for lung cancer, he has facilitated the approval and market launch of multiple targeted drugs both domestically and internationally. Professor Wu Yilong’s extensive development expertise, clinical advancement capabilities, and global perspective will significantly accelerate the clinical execution and global registration of two pipeline drugs, thereby expediting the availability of breakthrough treatment options for patients worldwide.

● GuanSIGNET●

SIGNET is a global pioneer in the “organoid + AI” drug discovery and development model. Recognized as a Shenzhen-based “Specialized, Refined, Distinctive, and Innovative” enterprise, it has also been accredited as a National High-Tech Enterprise. Originally incubated at Harvard University, SIGNET officially established its operations in Shenzhen in late 2020 and has since secured nearly RMB 300 million in financing and project grants. The company currently maintains four drug pipelines. Its lead pipeline focuses on SIGX1094, the world’s first targeted therapy for diffuse gastric cancer. SIGX1094 has received Investigational New Drug (IND) approvals from both the U.S. Food and Drug Administration (FDA) and China’s National Medical Products Administration (NMPA). Additionally, it has been granted Orphan Drug Designation and Fast Track Designation by the U.S. FDA, and has entered Phase I clinical trials.SIGNET is not only a phonetic transliteration of “Signet,” but also embodies the vision of “Harboring Hope, Pursuing Knowledge through Investigation.” The company leverages the critical role of organoid disease models—closely recapitulating patient genomic profiles—in drug efficacy evaluation and novel target discovery. By integrating AI-driven screening, synthesis, and optimization of small-molecule compounds, SIGNET develops first-in-class innovative targeted therapies. 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, thereby fully validating the forward-looking nature and scientific rigor of its technological strategy.