Small‐molecule Effectors of DNA Repair Proteins: Applications for Development of Cancer Therapeutics and Research

Abstract

A ubiquitous aspect of cellular life is the need to repair the many deleterious DNA lesions that arise due to environmental damage and as byproducts of normal cellular metabolism. The same DNA repair processes, which are critical for life, are also employed by cancer cells in their resistance to radiation and DNA‐damaging therapies. Inhibition of DNA repair or entrapment of the toxic DNA repair intermediates with the help of small molecules has both potential therapeutic and research utility. Although many proteins that maintain genome integrity and repair DNA damage appear to be attractive targets, they lack well‐defined small‐molecule binding determinants and clear structure–activity relationships. This article summarizes a number of studies that have led to the identification of small‐molecule drug lead compounds, which may also be useful in dissecting complex DNA repair networks. Systems that are particularly noteworthy are inhibition of PARP1, as it is a paradigm case for achieving successful clinical applications, and the emerging targets RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase.

Therapeutic disruption of RAD52–ssDNA complexation via novel drug-like inhibitors

“…In this study we have successfully overcome several challenges in developing drug-like small molecule inhibitors of an attractive anticancer drug target, human DNA repair protein RAD52. The main challenge rested in the necessity to disrupt an extensive and multivalent interaction between RAD52 and ssDNA, as RAD52 can accommodate approximately 44 nucleotides of ssDNA (4 nt per monomer in an undecameric protein ring) and utilizes two distinct DNA binding sites ( 3 , 9 ). Another important challenge was to develop a strategy that yields inhibitors that are specific to RAD52 over other ssDNA binding proteins, such as RPA, whose inhibition may be generally toxic to cells.…”

“…Another important challenge was to develop a strategy that yields inhibitors that are specific to RAD52 over other ssDNA binding proteins, such as RPA, whose inhibition may be generally toxic to cells. Finally, all the specifications mentioned above must be accomplished while remaining in drug-like chemical space (reviewed in ( 3 , 9 )).…”

“…Additionally, the very high hydrophilicity of epigallocatechins creates homogeneity problems in lipid formulations ( 74 ). Other RAD52 inhibitors have been shown to have a variety of additional ADME challenges (reviewed in ( 9 )). Our solution to overcoming challenges associated with current RAD52 inhibitors was to exploit the EGC pharmacophore, yet to do it from drug-like chemical space which is additionally synthetically tractable, which will facilitate SAR on the RAD52 system.…”

Human RAD52 double-ring remodels replication forks restricting fork reversal

“…While a validated and an attractive anticancer drug target 3,7,11,19,20,22,43,44 , the RAD52-DNA interaction is complex and agile, complicating selection of the structural features that can be targeted. The DNA binding areas within each RAD52 oligomeric ring are divided into an inner (primary) and outer (secondary) binding sites 25,[29][30][31] .…”

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

“…Once more, despite promising in vitro biological results, EGC and its analogues were characterized by poor ADME properties, largely due to low gut absorption, which was found to be further reduced when accompanied by food. Additionally, the very high hydrophilicity of EGC analogues created homogeneity problems in lipid formulations. , Very recently, Bhat and co-workers tried to overcome ADME challenges associated with EGC to produce new RAD52i . Pharmacophore information about the RAD52 complexation with EGC allowed for scaffold hopping into a drug-like synthetically accessible space.…”