DNA-dependent protein kinase (DNA-PK) inhibitors: Structure–activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain

Clapham, Kate M.; Bárdos, Julia; Finlay, M. Raymond V.; Golding, Bernard T.; Griffen, Edward J.; Griffin, Roger J.; Hardcastle, Ian R.; Menear, Keith; Ting, Attilla; Turner, Peter G.; Young, Gail L.; Cano, Céline

doi:10.1016/j.bmcl.2010.12.047

Cited by 24 publications

(14 citation statements)

References 18 publications

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“…Rapid metabolic clearance, instability, in vivo toxicity and off-target effects of wortmannin and LY294002 made further preclinical and clinical evaluation impractical (Collis, DeWeese, Jeggo, & Parker, 2005; Davidson, Amrein, Panasci, & Aloyz, 2013). However, LY294002 has been extensively utilized by KuDOS Pharmaceuticals Ltd. (UK) and Ihmaid et al as a lead compound for further modifications to improve specificity and efficacy to reduce off-target toxicities (Leahy et al, 2004; Clapham et al, 2011; Munck et al, 2012; Ihmaid, Al-Rawi, Bradley, Angove, & Robertson, 2012; Andrs et al, 2015). …”

Section: : Targeting Dna Double Strand Break Repair and Radiation Thmentioning

confidence: 99%

DNA repair targeted therapy: The past or future of cancer treatment?

Gavande

VanderVere-Carozza

Hinshaw

et al. 2016

Pharmacology & Therapeutics

332

282

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The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.

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Section: : Targeting Dna Double Strand Break Repair and Radiation Thmentioning

confidence: 99%

DNA repair targeted therapy: The past or future of cancer treatment?

Gavande

VanderVere-Carozza

Hinshaw

et al. 2016

Pharmacology & Therapeutics

332

282

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“…Rapid metabolic clearance (1 h), in vivo toxicity, and lack of specificity make clinical evaluation unfeasible in humans. However, LY294002 has proven to be a productive lead compound and biochemical modifications have produced a series of compounds with more favorable properties (Fuhrman et al, 2008; Clapham et al, 2011). These modifications using LY294002 as template have improved specificity with regards to DNA-PK inhibition (Ihmaid et al, 2011).…”

Section: Dna-pk Inhibitorsmentioning

confidence: 99%

Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond

Davidson¹,

Amrein²,

Panasci³

et al. 2013

Front. Pharmacol.

144

127

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Many current chemotherapies function by damaging genomic DNA in rapidly dividing cells ultimately leading to cell death. This therapeutic approach differentially targets cancer cells that generally display rapid cell division compared to normal tissue cells. However, although these treatments are initially effective in arresting tumor growth and reducing tumor burden, resistance and disease progression eventually occur. A major mechanism underlying this resistance is increased levels of cellular DNA repair. Most cells have complex mechanisms in place to repair DNA damage that occurs due to environmental exposures or normal metabolic processes. These systems, initially overwhelmed when faced with chemotherapy induced DNA damage, become more efficient under constant selective pressure and as a result chemotherapies become less effective. Thus, inhibiting DNA repair pathways using target specific small molecule inhibitors may overcome cellular resistance to DNA damaging chemotherapies. Non-homologous end joining a major mechanism for the repair of double-strand breaks (DSB) in DNA is regulated in part by the serine/threonine kinase, DNA dependent protein kinase (DNA-PK). The DNA-PK holoenzyme acts as a scaffold protein tethering broken DNA ends and recruiting other repair molecules. It also has enzymatic activity that may be involved in DNA damage signaling. Because of its’ central role in repair of DSBs, DNA-PK has been the focus of a number of small molecule studies. In these studies specific DNA-PK inhibitors have shown efficacy in synergizing chemotherapies in vitro. However, compounds currently known to specifically inhibit DNA-PK are limited by poor pharmacokinetics: these compounds have poor solubility and have high metabolic lability in vivo leading to short serum half-lives. Future improvement in DNA-PK inhibition will likely be achieved by designing new molecules based on the recently reported crystallographic structure of DNA-PK. Computer based drug design will not only assist in identifying novel functional moieties to replace the metabolically labile morpholino group but will also facilitate the design of molecules to target the DNA-PKcs/Ku80 interface or one of the autophosphorylation sites.

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“…By probing this presumed binding interaction further, replacement of the 3-phenyl group of 11 by an isosteric thiophen-2-yl substituent (15) improved DNA-PK inhibitory activity approximately 10-fold (DNA PK; IC 50 =18 nM) [32]. Homology modelling studies indicated that the heteroaryl substituent may occupy a putative hydrophobic pocket, with further SAR resulting in the discovery of O-alkoxyphenylchromen-4-one (16) (DNA PK; IC 50 =8 nM) [32,33].…”

Section: (Scheme 4)mentioning

confidence: 99%

“…In efforts to optimise the biological and pharmaceutical properties of 13, and to expand structure-activity relationships (SARs), the core chromenone scaffold as well as the dibenzothiophen-4-yl moiety have been systematically modified [32,33]. As 11 is approximately 10-fold more potent than the parent 8-phenylchromenone (3) this strongly indicated that the 3-phenyl substituent of 11 made additional binding interactions within the ATP-binding domain of DNA-PK.…”

Section: (Scheme 4)mentioning

confidence: 99%

Inhibition of the DNA-Dependent Protein Kinase for Cancer Therapy

Harnor¹,

Brennan²,

Cano³

2017

Med chem

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The catalytic activity of DNA-dependent protein kinase (DNA-PK) is central to its ability to repair lethal DNAdouble strand breaks (DSBs). This includes repair of DSB lesions following therapeutic treatment of cancer cells or resulting from oxidative stress or oncogene-induced transcription. As a tactic to induce tumour chemo-and radio-sensitisation, numerous attempts have been made to identify small molecule inhibitors of DNA-PK activity. This review examines the structures of known reversible and irreversible inhibitors, including those based upon chromen-4-one, arylmorpholine, and benzaldehyde scaffolds. VX-984 and M3814 are recent examples of DNA-PK catalytic inhibitors that have progressed into clinical development, the results from which should help to further advance our understanding of whether this approach represents a promising therapeutic strategy for the treatment of cancer.

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DNA-dependent protein kinase (DNA-PK) inhibitors: Structure–activity relationships for O-alkoxyphenylchromen-4-one probes of the ATP-binding domain

Cited by 24 publications

References 18 publications

DNA repair targeted therapy: The past or future of cancer treatment?

DNA repair targeted therapy: The past or future of cancer treatment?

Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond

Inhibition of the DNA-Dependent Protein Kinase for Cancer Therapy

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