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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Synthetic lethality and context-selective DNA-damage response dependencies: from genetic vulnerability to
Nayoon Jo1, Su-Jin Kang2, Jeongeun Kim1
1College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, the Republic of Korea; Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul 03760, the Republic of Korea.
Abstract:
Synthetic lethality has established DNA-damage response (DDR) dependencies as a major strategy for precision cancer therapy, exemplified by targeting BRCA1/2 and poly(ADP-ribose) polymerase (PARP). However, genetic dependency alone does not ensure pharmacological tractability or clinical utility. Emerging targets, including WRN, POLQ, USP1 and PARG, impose distinct requirements for ligandability, selectivity, target engagement, patient selection and the therapeutic window. A comparison of their structural biology, inhibitor chemotypes, SAR, pharmacodynamic strategies, resistance mechanisms and clinical development shows that successful translation requires matching a tumor-selective dependency to an experimentally validated, exposure-controllable pharmacological mechanism. This framework supports the rational prioritization of context-selective DDR dependencies beyond BRCA-PARP.
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