Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response. (August 2021)

• Record Type: Journal Article
• Authors: Wilson, David M.; Deacon, Ashley M.; Duncton, Matthew A.J.; Pellicena, Patricia; Georgiadis, Millie M.; Yeh, Andrew P.; Arvai, Andrew S.; Moiani, Davide; Tainer, John A.; Das, Debanu
• Is Part Of: Progress in biophysics and molecular biology. Volume 163(2021)
• Page Start: 130
• Page End: 142
• Publication Date: 2021-08
• Subjects: Fragment-based drug discovery -- Structure-based drug discovery -- X-ray crystallography -- Cancer therapeutics -- DNA damage Response -- DNA repair -- MRE11 -- APE1 -- FEN1; Biophysics -- Periodicals; Biochemistry -- Periodicals; Biophysics -- Periodicals; Molecular Biology -- Periodicals; Biophysique -- Périodiques; Biochimie -- Périodiques; 571.4
• DOI: 10.1016/j.pbiomolbio.2020.10.005
• Languages: English
• ISSNs: 0079-6107

Abstract

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).