Abstract
Non-homologous end joining (NHEJ) is one of the two principal damage repair pathways for DNA double-strand breaks in cells. In this review, we give a brief overview of the system including a discussion of the effects of deregulation of NHEJ components in carcinogenesis and resistance to cancer therapy. We then discuss the relevance of targeting NHEJ components pharmacologically as a potential cancer therapy and review previous approaches to orthosteric regulation of NHEJ factors. Given the limited success of previous investigations to develop inhibitors against individual components, we give a brief discussion of the recent advances in computational and structural biology that allow us to explore different targets, with a particular focus on modulating protein–protein interaction interfaces. We illustrate this discussion with three examples showcasing some current approaches to developing protein–protein interaction inhibitors to modulate the assembly of NHEJ multiprotein complexes in space and time.
Highlights
Background for Non-Homologous End Joining (NHEJ)Humans use the DNA-damage response (DDR) and DNA-repair pathways to repair the majority of the tens of thousands of DNA lesions that each of their cells experience each day [1]
A particular form of alternative-NHEJ pathway (A-NHEJ) is Microhomology-Mediated End Joining (MMEJ), a mutagenic-repair pathway that requires the presence of microhomology at the DNA ends [5]
What is certain is that many of these proteins are multi-faceted in character, forming various types of interactions with different NHEJ components, some of which may be present at allosteric binding sites that have not yet been considered fully but could act a further stepping-stone in the search for new drug molecules
Summary
Humans use the DNA-damage response (DDR) and DNA-repair pathways to repair the majority of the tens of thousands of DNA lesions that each of their cells experience each day [1]. Many of the specific DNA-PK inhibitors that target the ATP-binding site of the kinase domain are limited by poor solubility and high metabolic lability, with the most important strategy being to develop compounds based on existing drugs [38,39]. This is due to its ability to obtain high-resolution structures that reveal the electron density of small inhibitors or that of water molecules Such structure-guided fragment-based approaches have been used by our group over nearly two decades to identify druggable sites and new leads for targeting DNA double-strand-break repair through HR, for example targeting the BRCA2 binding site in RAD51 [99,100]. An advantage in exploiting this interaction in drug discovery is that, as argued above, targeting the NHEJ upon establishment of the DNA-PK complex minimises activation of alternative ‘rescue’ double-strand-break repair pathways. Colleagues where they used virtual screening against the LigIV C-terminal clamp domain resulting in the discovery of molecule #3101, which they showed inhibited LigIV–XRCC4 interaction in vitro [110], presenting a promising future route for the development of an allosteric NHEJ inhibitor
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