XtalPi and PharmaEngine Get Approvals for Phase I Trial of AI-Designed PRMT5 Inhibitor
XtalPi and PharmaEngine have received clearance from regulators in Taiwan and Australia to begin first-in-human testing of PEP08, an AI-designed second-generation PRMT5 inhibitor targeting solid tumors. The milestone also triggered a payment to XtalPi under the collaboration agreement between the two companies.
PEP08 was discovered using XtalPi’s integrated platform that combines quantum physics simulations, generative AI, and large-scale robotic experiments. The system reportedly produced a library of millions of compounds for PRMT5 and prioritized candidates with improved potency and selectivity. PharmaEngine then advanced the chosen preclinical candidate through IND-enabling studies.
PRMT5 (protein arginine methyltransferase 5) is a synthetic lethality target in cancers with homozygous MTAP deletion, a mutation present in an estimated 10–15% of tumors including including small cell lung cancer (NSCLC), mesothelioma, pancreatic cancer, glioblastoma multiforme (GBM), head and neck cancer, esophageal cancer, and bladder cancer. First-generation PRMT5 inhibitors have faced safety and selectivity challenges, limiting their clinical use.
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According to the press release citing preclinical data presented by PharmaEngine at the 2025 American Association for Cancer Research (AACR) Annual Meeting, PEP08 features a novel scaffold and an MTA-cooperative binding mode that enables selective inhibition of PRMT5 while sparing normal cells. The candidate demonstrated robust efficacy in animal models, favorable blood–brain barrier penetration, and an improved safety profile relative to earlier inhibitors.
The PRMT5 program builds on XtalPi’s broader platform capabilities. Founded in 2015 by MIT-trained physicists, the company applies quantum physics, AI, and robotics to drug and materials discovery. Its platform spans small molecules, biologics, antibody–drug conjugates, and molecular glues, integrating predictive physics models with large-scale AI molecular design and lab-in-the-loop automation for synthesis and validation.
In parallel with the PharmaEngine collaboration, XtalPi has expanded partnerships with large pharmaceutical companies, including Pfizer, to apply its physics- and AI-based methods to molecular modeling and binding affinity prediction. In August 2025, the company finalized a drug discovery agreement valued at up to $5.99 billion, one of the largest reported financial commitments to AI-driven pharmaceutical R&D.
With approvals from Australia’s Human Research Ethics Committee and Taiwan’s Food and Drug Administration, Phase I trials of PEP08 will now assess safety and tolerability in patients with advanced solid tumors.
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