XtalPi Inc. and PharmaEngine, Inc. have achieved a significant milestone in their AI-driven drug discovery collaboration with PEP08, a novel PRMT5 inhibitor, receiving regulatory clearances to initiate Phase 1 clinical trials in solid tumors. The approvals from Australia's Human Research Ethics Committee (HREC), recognized by the Australian Therapeutic Goods Administration (TGA), and the Taiwan Food and Drug Administration (TFDA) mark a pivotal advancement for the AI-designed therapeutic candidate.
Targeting a Critical Cancer Vulnerability
PRMT5 (Protein Arginine Methyltransferase 5) represents a validated synthetic lethality target in tumors harboring homozygous MTAP deletion, a genetic alteration associated with poor prognosis and present in 10-15% of human cancers. This includes small cell lung cancer (NSCLC), mesothelioma, pancreatic cancer, glioblastoma multiforme (GBM), head and neck cancer, esophageal cancer, and bladder cancer.
While PRMT5 inhibition offers a potent mechanism for targeted therapy, first-generation inhibitors have faced significant challenges in selectivity, resulting in dose-limiting toxicities and unmet medical needs. This therapeutic gap has driven the development of more selective second-generation compounds like PEP08.
AI-Powered Drug Design Platform
XtalPi leveraged its integrated drug discovery platform, which combines quantum physics, AI, and large-scale robotic experiments, to partner with PharmaEngine's scientific team in conducting de novo drug design. The AI platform generated a multi-million compound library for PRMT5, identifying novel lead series with exceptional potency and selectivity.
Following iterative optimization through quantum physics and AI-powered ADMET screening, PEP08 emerged as the preclinical candidate and advanced through IND-enabling studies conducted by PharmaEngine.
Superior Selectivity and Mechanism
As a second-generation PRMT5 inhibitor with a novel scaffold, PEP08 demonstrates superior activity and selectivity compared to earlier compounds. The drug's MTA-cooperative binding mode stabilizes a ternary complex with PRMT5, enabling highly selective target inhibition. This mechanism drives potent synthetic lethality efficacy against MTAP-deleted tumor cells while minimizing off-target effects on normal cells.
Promising Preclinical Profile
Preclinical studies revealed PEP08's markedly improved safety profile compared to first-generation PRMT5 inhibitors, alongside favorable blood-brain barrier penetration and overall developability characteristics. The compound achieved robust in vivo efficacy across multiple animal models.
Compared to other clinical-stage second-generation candidates, PEP08 exhibits potential best-in-class properties and compelling combination therapy opportunities. PharmaEngine presented these findings at the 2025 American Association for Cancer Research (AACR) Annual Meeting.
Partnership Milestone
The successful regulatory clearance and milestone achievement underscore XtalPi's platform-driven innovation capabilities and mark a pivotal advancement in its partnership with PharmaEngine. The milestone triggered a payment to XtalPi under the partnership agreement, demonstrating the commercial viability of AI-powered drug discovery approaches.
XtalPi, founded in 2015 by three physicists from MIT, provides digital and intelligent R&D solutions through its platform that integrates first-principles calculations, AI algorithms, high-performance cloud computing, and standardized automation systems. PharmaEngine, headquartered in Taipei and operating since 2003, focuses on new drug development and has one commercial product, ONIVYDE®, approved for metastatic pancreatic adenocarcinoma treatment.
