Defects in the DNA damage response (DDR) pathway drive genomic instability, promoting cancer initiation and uncontrolled cell proliferation. At the same time, these alterations create therapeutic vulnerabilities that can be selectively exploited in oncology.
Life Chemicals has developed a comprehensive portfolio of DNA Damage Repair Protein Libraries designed for targeting genomic stability pathways in oncology drug discovery. Structure-based and ligand-based selection strategies were applied to provide a selection of PAINS-free drug-like molecules for HTS and downstream medicinal chemistry efforts:
- DNA Damage Repair Focused Screening Set (59,600 compounds)
- DNA Damage Repair Targeted Screening Set (14,800 compounds)
The compound selection can be customized based on your requirements. Cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Scientific Rationale
The DNA Damage Response (DDR) is a highly conserved cellular network that safeguards genomic stability by detecting DNA lesions, activating cell cycle checkpoints, and coordinating DNA repair mechanisms. Dysfunction in DDR pathways is a hallmark of many cancers, creating therapeutic vulnerabilities that can be exploited through targeted inhibition [2].
Key DDR proteins include sensors (PARP1 and the MRN complex), transducer kinases (ATM, ATR, and DNA-PK) and downstream transducers and effectors (CHK1/CHK2, WEE1, BRCA1/2 and RAD51), forming a complex but highly druggable landscape for targeted cancer therapy. [1]. The clinical success of PARP inhibitors has validated DDR modulation as a powerful strategy, particularly in tumors with BRCA1/2 mutations or homologous recombination deficiency (HRD).
Current research addresses both monotherapy and combination regimens, with growing focus on biomarker-driven patient selection, isoform selectivity and overcoming resistance mechanisms, such as restoration of homologous recombination [3].
Therapeutic strategies targeting DDR proteins include:
- Synthetic lethality (e.g., PARP inhibition in HR-deficient tumors)
- Checkpoint inhibition (ATR, CHK1, WEE1 inhibitors inducing mitotic catastrophe)
- DNA repair sensitization (DNA-PK inhibitors enhancing radio- and chemosensitivity)
DNA Damage Repair Focused Screening Set (59,600 compounds)
This broad pathway-oriented DDR-focused screening set covers small molecules with predicted activity towards a wide spectrum of DDR-associated proteins. It enables exploration of both established and emerging DDR targets to identify novel modulators across homologous recombination (HR), non-homologous end joining (NHEJ), replication stress response and cell cycle checkpoint regulation. It is an ideal starting point for phenotypic screening, pathway modulation studies and discovery of first-in-class inhibitors.
To prepare this DDR-focused Screening Library, a reference set of DDR-associated proteins was first assembled. Bioactivity data for 175 DDR-relevant proteins were extracted from the ChEMBL. Inactive, low-confidence, and duplicate compounds were removed. Then, an ECFP-based 2D similarity search (Tanimoto ≥ 0.8) was performed against the proprietary HTS Compound Collection. PAINS, structural liabilities, and low-diversity chemotypes were filtered out. The final screening set consists of over 59,600 chemically diverse, drug-like compounds with high predicted relevance to DDR pathways.
Representative screening compounds from the DDR-focused Screening Library
DNA Damage Repair Targeted Screening Set (14,800 compounds)
To prepare this Target-specific DNA Damage Repair Screening Set, virtual screening was performed against highly-promising therapeutic targets in DDR regulation, which are actively investigated in oncology pipelines for synthetic lethality, replication stress exploitation, and resistance-overcoming strategies. This structure-guided design provided over 14,800 structurally diverse screening molecules with predicted binding affinity and preserved interaction profiles against the following DDR-related targets:
First, crystal structures from the Protein Data Bank were carefully prepared, including optimization of protonation states, addition of missing residues or side chains, removal of crystallographic artifacts and validation of the integrity of the respective active or binding sites. Docking workflows were benchmarked using known active reference compounds to ensure predictive reliability, after which large-scale high-throughput virtual screening was performed across diverse chemical space. Interaction fingerprints were generated to preserve key binding interactions.
Hits were refined via extra-precision docking. In-house MedChem filtering removed PAINS, assay-interfering structures and highly similar chemotypes. The resulting target-focused sets represent chemically diverse, drug-like compounds with predicted binding potential and reduced risk of assay interference.
RAD51
RAD51 is a recombinase essential for homologous recombination (HR), facilitating homology search and strand invasion during double-strand break repair. It forms nucleoprotein filaments on single-stranded DNA, enabling high-fidelity repair [4]. However, many cancer cells are heavily dependent on RAD51 overexpression to tolerate replication stress and genomic instability. Targeting RAD51 suppresses HR capacity, induces synthetic lethality in tumors deficient in alternative repair pathways (e.g., BRCA1/2 mutations) and sensitizes cancers to DNA-damaging therapies, such as platinum drugs and PARP inhibitors.
Key features:
- Method: SP (standard precision) ligand-receptor docking
- X-Ray data used: 7EJC
- MSD of re-docked reference compound: 0.274
- Binding affinity of re-docked reference compound: -4.93/-43.24
(Docking score/MMGBSA, kcal/mol) - Number of compounds selected: 3339
Figure 1. Spatial structure binding site of the complex of RAD51 with lead docking molecule F1064-0132.
DNA polymerase theta (POLQ)
DNA polymerase theta (POLQ) is a specialized, low-fidelity polymerase critical for theta-mediated end joining (TMEJ), an error-prone backup pathway for repairing double-strand breaks. Tumors deficient in HR (e.g., BRCA-mutated) become highly dependent on POLQ-mediated repair for survival. [5] Targeting POLQ selectively kills these HR-deficient cancers through synthetic lethality while sparing normal cells. Moreover, POLQ inhibition not only induces toxic DNA damage but also enhances the efficacy of PARP inhibitors, establishing it as a promising therapeutic target in DNA Damage Response.
Key features:
- Method: SP (standard precision) ligand-receptor docking
- X-Ray data used: 9BP9
- RMSD of re-docked reference compound: 0.448
- Binding affinity of re-docked reference compound: -8.2/-31.97 (Docking score/MMGBSA, kcal/mol)
- Number of compounds selected: 4074
Figure 2. Spatial structure binding site of the complex of PolQ with lead docking molecule F0545-1058.
WRN (Werner syndrome helicase)
WRN (Werner syndrome helicase) is a RecQ helicase with exonuclease activity involved in DNA replication, repair and telomere maintenance. It plays a particularly vital role in resolving replication stress and maintaining genome stability in microsatellite instability-high (MSI-H) cancers. Loss of WRN function leads to catastrophic genome instability in MSI-H cells, a vulnerability that can be exploited therapeutically.[6] Thus, WRN inhibition represents a context-specific DDR target, offering selective lethality in tumors with mismatch repair deficiency while sparing normal tissues.
Key features:
- Method: SP (standard precision) ligand-receptor docking
- X-Ray data used: 8PFO
- RMSD of re-docked reference compound: 1.97
- Binding affinity of re-docked reference compound: -19.03/-64.92 (Docking score/MMGBSA, kcal/mol)
- Number of compounds selected: 4780
Figure 3. Spatial structure binding site of the complex of WRN with lead docking molecule F3165-0544.
USP1 (ubiquitin-specific protease 1)
USP1 (ubiquitin-specific protease 1) is a deubiquitinase that regulates the Fanconi anemia pathway and translesion synthesis by removing ubiquitin from FANCD2 and PCNA. Through this regulation, USP1 controls repair of interstrand cross-links and tolerance of replication-blocking lesions. Many cancers exploit USP1 to maintain replication fork stability under stress. [7] Inhibiting USP1 destabilizes DNA repair complexes, leading to persistent DNA damage and sensitization to chemotherapy and PARP inhibition. Its druggability as a deubiquitinase makes USP1 a promising DDR target to disrupt tumor-specific DNA repair dependencies.
Key features:
- Method: SP (standard precision) ligand-receptor docking
- X-Ray data used: 9FCJ
- RMSD of re-docked reference compound: 0.259
- Binding affinity of re-docked reference compound: -13.12/-98.07 (Docking score/MMGBSA, kcal/mol)
- Number of compounds selected: 2634
Figure 4. Spatial structure binding site of the complex of USP1 with lead docking molecule F3165-0544.
Figure 5. Example of interacting fingerprints matrix comparison for stock compounds and reference set.
Figure 6. Distribution of compounds from reference and docking sets in the RAD51 targeted library. We can observe the emergence of new characteristic chemotype clusters while conserving the interaction mechanism.
Reference:
- Jackson, Stephen P, and Jiri Bartek. “The DNA-damage response in human biology and disease.” Nature vol. 461,7267 (2009): 1071-8. doi:10.1038/nature08467
- Drew, Yvette et al. “DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications.” Nature reviews. Drug discovery vol. 24,1 (2025): 19-39. doi:10.1038/s41573-024-01060-w
- Groelly, Florian J et al. “Targeting DNA damage response pathways in cancer.” Nature reviews. Cancer vol. 23,2 (2023): 78-94. doi:10.1038/s41568-022-00535-5
- Belan, Ondrej et al. “Single-molecule analysis reveals cooperative stimulation of Rad51 filament nucleation and growth by mediator proteins.” Molecular cell vol. 81,5 (2021): 1058-1073.e7. doi:10.1016/j.molcel.2020.12.020
- Wood, Richard D, and Sylvie Doublié. “DNA polymerase θ (POLQ), double-strand break repair, and cancer.” DNA repair vol. 44 (2016): 22-32. doi:10.1016/j.dnarep.2016.05.003
- Baltgalvis, Kristen A et al. “Chemoproteomic discovery of a covalent allosteric inhibitor of WRN helicase.” Nature vol. 629,8011 (2024): 435-442. doi:10.1038/s41586-024-07318-y
- Wang, Longhao et al. “Inhibition of USP1 activates ER stress through Ubi-protein aggregation to induce autophagy and apoptosis in HCC.” Cell death & disease vol. 13,11 951. 10 Nov. 2022, doi:10.1038/s41419-022-05341-3