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ShenzhenJune 2, 2026 /PRNewswire/ — Recently, XtalPi (2228.HK) and its incubated company Signet Therapeutics reached another collaboration milestone. The pan-TEAD inhibitor SIGX2649, discovered through their partnership, received an Investigational New Drug (IND) approval from the U.S. Food and Drug Administration (FDA) ahead of schedule. Phase I clinical trials are planned to commence as early as the third quarter of this year. SIGX2649 is the first potent pan-TEAD inhibitor to fully cover all four subtypes of the TEAD family, and it is expected to become the world’s first marketed pan-TEAD inhibitor targeting the Hippo pathway, holding broad market potential in the treatment of solid tumors. Following the clinical approval of SIGX1094, the world’s first targeted therapy for diffuse gastric cancer, the early approval of this second innovative pipeline from XtalPi and Signet Therapeutics marks a continued clinical validation of the “AI + organoid” drug discovery strategy, demonstrating the replicability of this successful model.
The early IND approval of SIGX2649 fully reflects the urgent clinical need for this pipeline. Its core preclinical study data demonstrate excellent druggability, safety, and differentiated clinical value. Additionally, Professor Yi-Long Wu, Chief Expert at Guangdong Provincial People’s Hospital and a leading figure in precision lung cancer treatment in China, will serve as the Leading Principal Investigator (Leading 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, accelerating the global development of these two core pipelines.
The consecutive success of multiple pipelines under development by XtalPi and Signet Therapeutics strongly validates the rapid “from algorithm to clinic” translation capability of their underlying R&D platform, as well as the immense 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 a commercialization revenue share of up to double-digit percentages from SIGX2649.
The TEAD protein is a core node of the Hippo signaling pathway, which, alongside P53, RAS, and others, is considered a key oncogenic driver pathway. It holds broad prospects for treating solid tumors such as mesothelioma, liver cancer, and lung cancer, but has long lacked effective drugs. The TEAD protein family comprises four subtypes with distinct functions and expression patterns. Inhibitors must strike a delicate balance between potently inhibiting each subtype and ensuring safety, making this a highly challenging endeavor. Currently, no TEAD inhibitor has been approved for marketing worldwide, with the most advanced candidates still in Phase I clinical trials.
SIGX2649 is a pan-TEAD (TEAD 1-4) inhibitor co-developed by XtalPi and Signet Therapeutics based on the “AI + organoid” model. It simultaneously targets all four subtypes of the TEAD family, demonstrating broad clinical development prospects. Its dual mechanism of action—inhibiting TEAD palmitoylation while enhancing the binding of VGLL4 to TEAD—further amplifies the drug’s suppression of YAP/TEAD function. Preclinical studies show that SIGX2649 exhibits excellent anti-proliferative activity in various in vitro tumor models (including liver cancer organoids and mesothelioma), significant in vivo tumor inhibition, favorable pharmacokinetics, and lower renal-targeted toxicity compared to similar investigational drugs, offering differentiated clinical advantages and best-in-class therapeutic potential.
SIGX2649 is expected to demonstrate significant therapeutic efficacy in advanced solid tumors with substantial unmet clinical needs, such as small cell lung cancer, mesothelioma, and liver cancer. Furthermore, in combination with RAS pathway inhibitors, it shows notable synergistic effects in KRAS-mutant solid tumors, including non-small cell lung cancer and colorectal cancer. Based on these outstanding data, the core preclinical study of SIGX2649 has been selected for presentation at the 2026 Annual Meeting of the American Association for Cancer Research (AACR), one of the world’s most authoritative and influential cancer research conferences.
During the discovery of SIGX2649, XtalPi leveraged its quantum physics, AI, and automated synthesis platform to achieve a rapid closed loop between virtual screening and physical synthesis. XtalPi first used AI to generate a library of millions of molecules and applied computational chemistry for multidimensional evaluation of key properties such as activity, subtype selectivity, structural novelty, and synthesizability, quickly converging the library to hundreds of molecules. Subsequently, robot-driven large-scale chemical synthesis and testing efficiently completed the “Design-Make-Test-Analyze” (DMTA) closed-loop validation. Building on this, XtalPi combined Signet Therapeutics’ organoid model screening to obtain lead compounds with novel scaffolds. Through iterative ADMET optimization using physical models and AI, and final validation of in vivo efficacy and safety, SIGX2649 was identified as the preclinical candidate compound (PCC).
Previously, SIGX1094, the world’s first “AI + organoid” drug and the first FAK/SRC dual-target inhibitor to enter clinical trials, co-developed by XtalPi and Signet Therapeutics, received Orphan Drug Designation and Fast Track Designation from the U.S. FDA, and was nominated for the 2025 Prix Galien USA. It is currently undergoing Phase I clinical trials for diffuse gastric cancer at Peking University Cancer Hospital and is about to initiate Phase II. The pace and quality of this molecule’s progression from discovery to IND provided direct experience and platform validation for the rapid approval of SIGX2649. The sequential entry of both molecules into clinical trials under the “AI + organoid” R&D model, with the second pipeline receiving early approval, once again confirms that the “AI + organoid” platform collaboration model between XtalPi and Signet Therapeutics possesses reproducible and scalable technical advantages in molecular generation, selectivity optimization, and druggability assessment.
Professor Yi-Long Wu, who will serve as the Leading 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, is not only the Chief Expert at Guangdong Provincial People’s Hospital but also a recipient of the International Association for the Study of Lung Cancer (IASLC) Distinguished Scientific Award. With nearly 40 years of experience in precision lung cancer treatment research, he has facilitated the approval and marketing of multiple targeted drugs both domestically and internationally. Professor Wu’s extensive development experience, clinical advancement capabilities, and international perspective will significantly accelerate the clinical execution and global registration of these two pipeline drugs, expediting the delivery of breakthrough treatments to patients worldwide.
About Signet Therapeutics
Signet Therapeutics is a global pioneer in the “organoid + AI” drug discovery model. It is recognized as a specialized and innovative enterprise in Shenzhen and has obtained national high-tech enterprise certification. Originally founded at Harvard University, the company officially established its operations in Shenzhen at the end of 2020 and has since secured nearly 300 million RMB in funding and project grants. The company currently has four drug pipelines. Its first pipeline develops SIGX1094, the world’s first targeted therapy for diffuse gastric cancer, which has received IND approvals from both the U.S. FDA and China’s NMPA, as well as Orphan Drug Designation and Fast Track Designation from the U.S. FDA, and has entered Phase I clinical trials. “Signet” is not only a transliteration but also embodies the vision of “Full of Hope, Inquiring into Things to Acquire Knowledge.” The company leverages the critical role of organoid disease models that closely mimic patient genomic characteristics in drug efficacy evaluation and new target discovery, combined with AI-driven screening, synthesis, and optimization of small molecule compounds, to develop first-in-class innovative targeted drugs. In April 2025, the U.S. FDA issued a formal statement supporting the gradual replacement of traditional animal experiments with organoid and AI technologies, fully validating the forward-looking and scientific nature of its technological strategy.
About XtalPi
XtalPi (“XtalPi Holdings Limited,” stock abbreviation: XtalPi Holdings, XTALPI, stock code: 2228.HK) was founded in 2015 by three physicists from the Massachusetts Institute of Technology. It is an innovative R&D platform based on quantum physics, empowered by artificial intelligence and driven by robotics. The company combines first-principles calculations based on quantum physics, artificial intelligence, high-performance cloud computing, and scalable, standardized robotic automation to provide drug and materials science R&D solutions and services to global and domestic companies in the pharmaceutical and materials science industries (including agricultural technology, energy, new chemicals, and cosmetics).