构建用于DNA损伤反应领域药物发现的整合平台

The DNA Damage Response (DDR) consists of a network of cellular pathways that recognize, signal, and repair different DNA lesions in coordination with other cellular activities. While DDR deregulation contributes to tumor initiation, it also confers therapeutic vulnerabilities specific to cancer cells. Currently, more than 50 chemotherapeutic drugs approved by FDA act primarily through general DNA damage mechanisms. Furthermore, the identification of synthetic lethal interactions in the last years has further paved the way for a new wave of precision drugs that target DDR. PARP inhibitors have revolutionized the treatment of patients with BRCA mutations. Similarly, WRN inhibition shows promising activity in microsatellite-unstable cancers, and ATR inhibition confers therapeutic benefit in ATM-deficient cancers. We have established an integrated platform designed to characterize and decipher the DDR defects and mechanisms associated with a specific target or pre-clinical drug candidates. Leveraging a comprehensive suite of biochemical assays, high content imaging multiplex panels that detect DNA damage and replication stress markers, GFP-based reporter assays for double strand break (DSB) repair, hematotoxicity and replication-related toxicity, and in vivo pharmacology DDR models for PK/PD and efficacy, we can support every stage of cancer drug discovery. Additionally, we have developed a knowledge-based DDR modelling tool to predict the impact of target depletion on the choice of DSB repair pathway and potentially identify novel synthetic lethal interactions. Using this in silico tool, we were able to recapitulate one of the mechanisms of resistance to PARP inhibition in BRCA deficient tumors. In conclusion, Evotec's comprehensive DDR toolkit enables mechanistic understanding of targets and drug candidates in the DDR network.