{"doi":"10.1016/j.pbiomolbio.2020.10.005","title":"Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response","abstract":"Cancer will directly affect the lives of over one-third of the population. The DNA Damage Response (DDR) is an intricate system involving damage recognition, cell cycle regulation, DNA repair, and ultimately cell fate determination, playing a central role in cancer etiology and therapy. Two primary therapeutic approaches involving DDR targeting include: combinatorial treatments employing anticancer genotoxic agents; and synthetic lethality, exploiting a sporadic DDR defect as a mechanism for cancer-specific therapy. Whereas, many DDR proteins have proven \"undruggable\", Fragment- and Structure-Based Drug Discovery (FBDD, SBDD) have advanced therapeutic agent identification and development. FBDD has led to 4 (with ∼50 more drugs under preclinical and clinical development), while SBDD is estimated to have contributed to the development of >200, FDA-approved medicines. Protein X-ray crystallography-based fragment library screening, especially for elusive or \"undruggable\" targets, allows for simultaneous generation of hits plus details of protein-ligand interactions and binding sites (orthosteric or allosteric) that inform chemical tractability, downstream biology, and intellectual property. Using a novel high-throughput crystallography-based fragment library screening platform, we screened five diverse proteins, yielding hit rates of ∼2-8% and crystal structures from ∼1.8 to 3.2 Å. We consider current FBDD/SBDD methods and some exemplary results of efforts to design inhibitors against the DDR nucleases meiotic recombination 11 (MRE11, a.k.a., MRE11A), apurinic/apyrimidinic endonuclease 1 (APE1, a.k.a., APEX1), and flap endonuclease 1 (FEN1).","journal":"Progress in Biophysics and Molecular Biology","year":2020,"id":93945,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":39,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":468845,"name":"Ashley M. Deacon","orcid":null,"position":1,"is_corresponding":false},{"id":468329,"name":"Matthew A. J. Duncton","orcid":"0000-0002-6007-7515","position":2,"is_corresponding":false},{"id":468330,"name":"Patricia Pellicena","orcid":"0000-0002-0575-4448","position":3,"is_corresponding":false},{"id":468331,"name":"Millie M. Georgiadis","orcid":"0000-0003-2976-4576","position":4,"is_corresponding":false},{"id":468846,"name":"Andrew Yeh","orcid":null,"position":5,"is_corresponding":false},{"id":50316,"name":"A.S. Arvai","orcid":null,"position":6,"is_corresponding":false},{"id":468332,"name":"Davide Moiani","orcid":"0000-0003-0715-8508","position":7,"is_corresponding":false},{"id":107262,"name":"John A. Tainer","orcid":"0000-0003-1659-2429","position":8,"is_corresponding":false},{"id":468333,"name":"Debanu Das","orcid":"0000-0001-6019-6760","position":9,"is_corresponding":false},{"id":184128,"name":"David M. Wilson","orcid":null,"position":0,"is_corresponding":true}],"reference_count":154,"raw_metadata":null,"created_at":"2026-07-18T22:31:34.149524Z","pmid":"33115610","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}