Wilson, David M., III.Deacon, Ashley M.Duncton, Matthew A. J.Pellicena, PatriciaGeorgiadis, Millie M.Yeh, Andrew P.Arvai, Andrew S.Moiani, DavideTainer, John A.Das, Debanu2022-04-082022-04-082021-08Wilson, D. M., Deacon, A. M., Duncton, M. A. J., Pellicena, P., Georgiadis, M. M., Yeh, A. P., Arvai, A. S., Moiani, D., Tainer, J. A., & Das, D. (2021). Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response. Progress in Biophysics and Molecular Biology, 163, 130–142. https://doi.org/10.1016/j.pbiomolbio.2020.10.0050079-6107https://hdl.handle.net/1805/28450Cancer 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).en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalCancer therapeuticsDNA damage ResponseDNA repairFEN1Fragment-based drug discoveryArticle