A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors
Pharmaron collaborated with Xrad Therapeutics and Duke University School of Medicine to support the discovery and hit-to-lead development of XRD-0394, a dual ATM/DNA-PK inhibitor targeting the DNA damage response. This kinase inhibitor XRD-0394 represents a significant advancement in cancer therapy, enhancing the cytotoxic effects of therapeutic ionizing radiation in both in vitro and in vivo models.
This study highlights the discovery and preliminary evaluation of XRD-0394, an orally administered compound that not only radiosensitizes cancer cells but also increases the activity of topoisomerase I inhibitors under laboratory conditions. Furthermore, XRD-0394 demonstrates single-agent efficacy in BRCA1/2-deficient cells and exhibits synergistic effects when combined with PARP inhibitors.
A Phase Ia clinical study (NCT05002140) evaluating kinase inhibitor XRD-0394 in combination with radiotherapy has been successfully completed, showcasing its potential in advanced cancer treatments.
Pharmaron played a pivotal role in this study by providing integrated drug discovery services, including:
- Design of novel target molecules using computer-aided drug discovery (CADD)
- Synthesis of newly designed compounds
- Evaluation of compounds’ in vitro activities
- DMPK studies on promising compounds
Molecular Cancer Therapeutics 2024, 23:1-15
DOI: 10.1158/1535-7163.MCT-23-0890
Access the publication at https://pubmed.ncbi.nlm.nih.gov/38588408/.