TY - JOUR
T1 - Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response
AU - Wilson, David M.
AU - Deacon, Ashley M.
AU - Duncton, Matthew A.J.
AU - Pellicena, Patricia
AU - Georgiadis, Millie M.
AU - Yeh, Andrew P.
AU - Arvai, Andrew S.
AU - Moiani, Davide
AU - Tainer, John A.
AU - Das, Debanu
N1 - Funding Information:
Research included in this publication was supported by the National Center For Advancing Translational Sciences of the NIH under Award Number R43 TR001736 , and the National Institute Of General Medical Sciences of the NIH under Award Number R44 GM132796 , to Accelero Biostructures Inc.; National Cancer Institute of the NIH under Award Number R43 CA254552 to XPose Therapeutics, Inc.; and NIH/NCI grants to John A. Tainer ( P01 CA092584 , R01 CA117638 , R01 CA200231 , and R35 CA220430 ). J.A.T. also acknowledges support by a Robert A. Welch Chemistry Chair, and the Cancer Prevention Research Institute of Texas (CPRIT) grants RP180813 and RP130397 . X-ray diffraction data encompassing the work in this manuscript were collected by Accelero Biostructures Inc. at Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, Menlo Park, California; and at the Berkeley Center for Structural Biology (BCSB) synchrotron beamlines at the Advanced Light Source (ALS), Lawrence Berkeley National Laboratory, Berkeley, California. Use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515 . The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences ( P41 GM103393 ). The BCSB is supported in part by the Howard Hughes Medical Institute . The ALS is a Department of Energy Office of Science User Facility under Contract No. DE-AC02-05CH11231 . The Pilatus detector on 5.0.1. was funded under NIH grant S 10 OD021832 . The ALS-ENABLE beamlines are supported in part by the National Institutes of Health, National Institute of General Medical Sciences ( P30 GM124169 ). Portions of this work (J.A.T) were also conducted at ALS through the Integrated Diffraction Analysis Technologies (IDAT) program, supported by DOE Office of Biological and Environmental Research with additional support from a High-End Instrumentation Grant ( S10 OD018483 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2020 The Authors
PY - 2021/8
Y1 - 2021/8
N2 - 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).
AB - 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).
KW - APE1
KW - Cancer therapeutics
KW - DNA damage Response
KW - DNA repair
KW - FEN1
KW - Fragment-based drug discovery
KW - MRE11
KW - Structure-based drug discovery
KW - X-ray crystallography
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U2 - 10.1016/j.pbiomolbio.2020.10.005
DO - 10.1016/j.pbiomolbio.2020.10.005
M3 - Article
C2 - 33115610
AN - SCOPUS:85096372189
SN - 0079-6107
VL - 163
SP - 130
EP - 142
JO - Progress in Biophysics and Molecular Biology
JF - Progress in Biophysics and Molecular Biology
ER -