XtalPi Inc. (2228.HK) today announced that PEP08, a next-generation PRMT5 inhibitor discovered in collaboration with PharmaEngine, Inc., has achieved a significant clinical development milestone. PEP08 has received approvals for Phase I clinical trials in solid tumors from the Australian Human Research Ethics Committee (HREC), the Australian Therapeutic Goods Administration (TGA), and local Food and Drug Administration of Taiwan region(TFDA). XtalPi has confirmed receipt of a milestone payment for this project.
PRMT5 (Protein Arginine Methyltransferase 5) is a key enzyme overexpressed in various cancers, driving tumor growth and serving as a prominent target for synthetic lethality in cancer therapy. In tumors with homozygous MTAP (Methylthioadenosine Phosphorylase) deletions—accounting for approximately 10-15% of human cancers—inhibiting PRMT5 can induce a “synthetic lethal” effect, offering the potential for highly effective and safe targeted cancer treatments. Such tumors are commonly found in non-small cell lung cancer (NSCLC), mesothelioma, pancreatic cancer, glioblastoma (GBM), head and neck cancer, esophageal cancer, and bladder cancer. However, traditional PRMT5 inhibitors often face toxicity issues due to poor selectivity, leaving significant unmet clinical needs.
Leveraging its integrated platform combining physics-based modeling, AI algorithms, and robotic experimentation, XtalPi collaborated with PharmaEngine’s expert team to rapidly advance the physicochemical design of PEP08. XtalPi generated a molecular library of millions of compounds, from which it precisely identified a set of lead compounds with exceptional drug activity, selectivity, and novel molecular scaffolds. Following multiple rounds of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) property evaluation and optimization using combined physics and AI models, PEP08 was selected as the preclinical candidate (PCC). PharmaEngine subsequently completed the preclinical development.
As a second-generation PRMT5 inhibitor, PEP08 features a novel structure with high activity and selectivity. It binds to PRMT5 via an MTA-cooperative mode, forming a stable ternary complex that achieves highly selective inhibition, specifically targeting MTAP-deficient tumor cells while minimizing impact on normal cells. This positions PEP08 as a promising candidate for clinical development.
Preclinical data demonstrate that PEP08 offers significant toxicity and safety advantages over first-generation non-selective PRMT5 inhibitors, with excellent blood-brain barrier penetration and optimal drug-like properties. In multiple animal efficacy models, PEP08 exhibited robust in vivo efficacy. Compared to other second-generation PRMT5 inhibitors in clinical development, PEP08 demonstrates potential best-in-class properties and broad prospects for combination therapies. These findings were presented by PharmaEngine at the 2025 American Association for Cancer Research (AACR) Annual Meeting.
The successful regulatory approvals for clinical trials in Australia and Taiwan, along with the milestone payment, mark a significant achievement in the collaboration between XtalPi and PharmaEngine, further validating XtalPi’s platform in efficiently enabling drug innovation. XtalPi will continue to leverage its AI- and robotics-driven drug discovery platform to support partners in accelerating the development of innovative, market-competitive drugs, delivering high-quality, effective treatment options to patients worldwide.
About PharmaEngine, Inc.
Founded in February 2003, PharmaEngine, Inc. operates under a “Virtual Pharmaceutical Company Business Model,” focusing on new drug development through international strategic alliances to mitigate development risks. Its marketed anticancer drug, ONIVYDE®, is approved in the United States, Europe, South Korea, Singapore, Japan, and China. Among its pipeline, PEP07, a cell damage regulatory enzyme inhibitor, is currently in Phase I clinical trials, while PEP08, an MTA-cooperative PRMT5 inhibitor, is poised to enter Phase I trials. Additionally, PharmaEngine advances early-stage drug development through international collaborations and licensing, leveraging its extensive project management expertise to expand its pipeline and accelerate drug development and commercialization.
