IDEAYA Demonstrates Preclinical Success with PRMT5 Inhibitor IDE892

IDE892 was designed through IDEAYA’s physics-based ligand design and optimization platform. Preclinical models demonstrated its highly selective antiproliferative activity against MTAP-deleted tumors, which comprise approximately 15% of all solid tumors. Notably, IDE892 achieved durable complete responses when combined with MAT2A inhibitor IDE397 in preclinical studies.

IDEAYA has initiated IND-enabling studies for IDE892, with plans to submit an Investigational New Drug (IND) application to the FDA by mid-2025. The candidate exhibits favorable drug-like properties—high potency, selectivity, and synergistic potential with MAT2A inhibition.

Yujiro S. Hata, CEO of IDEAYA, commented:

"IDE892 advances our strategy to combine PRMT5 and MAT2A mechanisms, potentially enhancing efficacy for MTAP-deleted solid tumors through a rational combination approach."

Dr. Michael White, Chief Scientific Officer at IDEAYA, emphasized:

"Through iterative design and lead optimization, we’ve achieved a best-in-class target profile for the PRMT5 program with IDE892."

Synthetic Lethality

IDEAYA Biosciences has built a fully integrated platform to advance synthetic lethality as a promising therapeutic strategy in oncology. Synthetic lethality occurs when the simultaneous loss of two genes results in cell death, while the loss of either gene alone has no significant effect on cell viability. This concept is leveraged to selectively target cancer cells that harbor specific genetic alterations, sparing normal cells.

Figure: IDEAYA Biosciences

Key Components of the Platform

1. Target Discovery and Validation
   IDEAYA utilizes a dual CRISPR library approach, developed in collaboration with the University of California, San Diego, to screen for synthetic lethal interactions. This library focuses on known tumor suppressor genes and potential synthetic lethal partners. By systematically knocking out gene pairs in cancer cell lines, IDEAYA identifies gene dependencies unique to cancer cells.

   Another layer of target discovery comes from the PAGEO platform, developed with the Broad Institute, which examines functionally redundant paralogous genes in ovarian cancer. These proprietary datasets are complemented by access to public resources, including The Cancer Genome Atlas (TCGA) and Project GENIE.

2. Bioinformatics Integration
   Advanced bioinformatics capabilities play a central role in IDEAYA’s platform. The company integrates data from its proprietary and public datasets using machine learning algorithms to identify robust synthetic lethality interactions. This computational power helps prioritize targets based on biological relevance and druggability.

3. Drug Development and Biomarker Discovery
   IDEAYA’s approach extends beyond target identification to the discovery and validation of therapeutic compounds. Parallel biomarker research identifies genetic signatures that predict patient responses to these therapies. This integration ensures that therapies are developed for well-defined patient populations, increasing the likelihood of clinical success.

4. Preclinical Models and Translation
   In vitro and in vivo models validate targets and test the efficacy of synthetic lethality inhibitors. These models are chosen based on computational insights and enable translational research that connects preclinical findings to clinical applications.

Applications in Oncology

IDEAYA’s synthetic lethality platform focuses on addressing key genetic vulnerabilities in cancer. Examples include targeting MAT2A in tumors with MTAP deletions, PARG in homologous recombination-deficient tumors, and Werner Helicase in microsatellite instability-high (MSI-H) cancers. By focusing on defined patient populations, IDEAYA’s therapies aim to maximize precision and impact.

IDEAYA specializes in precision oncology, focusing on synthetic lethality to develop targeted therapeutics. Its pipeline includes multiple clinical and preclinical programs addressing biomarker-selected cancers. Headquartered in South San Francisco, the company integrates biomarker discovery and drug development to improve outcomes for cancer patients.