Abstract
Personalized medicine and therapies represent the goal of modern medicine, as drug discovery strives to move away from one-cure-for-all and makes use of the various targets and biomarkers within differing disease areas. This approach, especially in oncology, is often undermined when the cells make use of alternative survival pathways. As such, acquired resistance is unfortunately common. In order to combat this phenomenon, synthetic lethality is being investigated, making use of existing genetic fragilities within the cancer cell. This Perspective highlights exciting targets within synthetic lethality, (PARP, ATR, ATM, DNA-PKcs, WEE1, CDK12, RAD51, RAD52, and PD-1) and discusses the medicinal chemistry programs being used to interrogate them, the challenges these programs face, and what the future holds for this promising field.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Ataxia Telangiectasia Mutated Proteins / genetics
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Cell Cycle Proteins / antagonists & inhibitors
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Cyclin-Dependent Kinases / antagonists & inhibitors
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DNA-Activated Protein Kinase / antagonists & inhibitors
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Genes, BRCA2
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Humans
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Neoplasms / genetics
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Neoplasms / therapy
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Poly(ADP-ribose) Polymerases / genetics
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Precision Medicine
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Protein Kinase Inhibitors / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Rad51 Recombinase / genetics
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Synthetic Lethal Mutations*
Substances
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Cell Cycle Proteins
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Protein Kinase Inhibitors
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Poly(ADP-ribose) Polymerases
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Protein-Tyrosine Kinases
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WEE1 protein, human
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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DNA-Activated Protein Kinase
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CDK12 protein, human
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Cyclin-Dependent Kinases
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RAD51 protein, human
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Rad51 Recombinase