1-Substituted (Dibenzo[<i>b,d</i>]thiophen-4-yl)-2-morpholino-4<i>H</i>-chromen-4-ones Endowed with Dual DNA-PK/PI3-K Inhibitory Activity

Cano, Céline; Saravanan, Kappusamy; Bailey, Chris; Bárdos, Julia; Curtin, Nicola J.; Frigerio, Mark; Golding, Bernard T.; Hardcastle, Ian R.; Hummersone, Marc; Menear, Keith; Newell, David R.; Richardson, Caroline; Shea, Kerry; Smith, Graeme C.M.; Thömmes, Pia; Ting, Attilla; Griffin, Roger J.

doi:10.1021/jm400915j

Cited by 48 publications

(38 citation statements)

References 30 publications

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“…The newly synthesised compounds all possessed polar substituents at the dibenzothiophene 1-position, with an aim to improve potency and physicochemical properties [30]. A number of the compounds exhibited high potency against DNA-PK and potentiated the cytotoxicity of IR in vitro 10-fold or more (e.g., 14; DNA-PK IC 50 =5.0 ± 1 nM, IR dose modification ratio=13).…”

Section: (Scheme 4)mentioning

confidence: 99%

“…Furthermore, 14 was shown to potentiate not only IR in vitro but also DNA-inducing cytotoxic anticancer agents, both in vitro and in vivo. A counter-screen against other members of the PI3K PIKK family revealed that some of the compounds were potent mixed DNA-PK and PI3K inhibitors, including 14 [30,31]. The favourable biological activity of 14 was complemented by superior drug-like properties compared to NU7441 (13), and acceptable plasma protein binding, combined with weak activity against hERG and a panel of cytochrome P450 (CYP) drug-metabolising enzymes (Table 4) [30].…”

Section: (Scheme 4)mentioning

confidence: 99%

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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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Section: (Scheme 4)mentioning

confidence: 99%

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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“…[a] Data are the mean±SD or individual values; adapted from Cano et al . [b] DMR: dose modification ratio, defined as the percentage of cell survival in the absence of compound with 2 Gy treatment divided by that in the presence of compound plus 2 Gy treatment as determined in 6‐ to 8‐day clonogenic assays.…”

Section: Small‐molecule Inhibitors Of Dna‐pk Activitymentioning

confidence: 99%

Targeting DNA‐Dependent Protein Kinase for Cancer Therapy

2017

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The catalytic activity of DNA‐dependent protein kinase (DNA‐PK) is critical to its ability to repair lethal DNA double‐strand breaks (DSBs). This includes repair of DSB lesions resulting from oxidative stress, oncogene‐induced transcription, or following therapeutic treatment of cancer cells. Armed with this knowledge, many attempts have been made to identify small‐molecule inhibitors of DNA‐PK activity as an approach to induce tumour chemo‐ and radiosensitisation. This review examines the structures of known reversible and irreversible inhibitors, including those based on chromen‐4‐one, arylmorpholine, and benzaldehyde scaffolds. DNA‐PK catalytic inhibitors, such as VX‐984 (8‐[(1S)‐2‐[[6‐(4,6‐dideuterio‐2‐methylpyrimidin‐5‐yl)pyrimidin‐4‐yl]amino]‐1‐methylethyl]quinoline‐4‐carboxamide) and M3814 ((S)‐[2‐chloro‐4‐fluoro‐5‐(7‐morpholinoquinazolin‐4‐yl)phenyl]‐(6‐methoxypyridazin‐3‐yl)methanol), have now progressed into clinical development which should help to further advance our understanding of whether this approach is a promising therapeutic strategy for the treatment of cancer.

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“…25 The two nitrophenyl derivatives (15,16) were then quantitatively reduced by zinc in acetic acid to the corresponding amino derivatives (18,19). 26 …”

Section: Chemistrymentioning

confidence: 99%

Novel caffeine derivatives with antiproliferative activity

et al. 2016

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Caffeine is probably the best known and most widely used psychoactive substance in the world. Beside its psychoactive effects, caffeine has been found to affect the cell cycle and DNA repair, as a consequence of the inhibition of ATM and ATR kinases. These two DNA damage response kinases, members of the phosphatidylinositol 3-kinase related protein kinase family, represent very attractive anticancer drug targets. Their inhibition can selectively sensitize cancer cells to DNA damaging agents and even kill various tumour cells in monotherapy. We developed a series of caffeine derivatives and evaluated their antiproliferative effects on 11 human tumour cell lines and compared them against caffeine and a standard ATR inhibitor VE-821. Although new caffeine derivatives did not achieve the overall potency of VE-821, several compounds exhibited enhanced antiproliferative activity compared to caffeine and in some cell lines showed at least comparable activity to VE-821.

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1-Substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones Endowed with Dual DNA-PK/PI3-K Inhibitory Activity

Cited by 48 publications

References 30 publications

Inhibition of the DNA-Dependent Protein Kinase for Cancer Therapy

Inhibition of the DNA-Dependent Protein Kinase for Cancer Therapy

Targeting DNA‐Dependent Protein Kinase for Cancer Therapy

Novel caffeine derivatives with antiproliferative activity

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