Discovery of 4-{4-[(3<i>R</i>)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1<i>H</i>-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity

Foote, Kevin M.; Blades, Kevin; Cronin, Anna; Fillery, Shaun; Guichard, Sylvie S.; Hassall, Lorraine; Hickson, Ian; Jacq, Xavier; Jewsbury, Philip J.; McGuire, Thomas M.; Nissink, J. Willem M.; Odedra, Rajesh; Page, Ken; Perkins, Paula; Suleman, Abid; Tam, Kin Yip; Thömmes, Pia; Broadhurst, Rebecca; Wood, Christine

doi:10.1021/jm301859s

Cited by 196 publications

(175 citation statements)

References 40 publications

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“…We also demonstrated that pDNA-PKcs provided a functional, sensitive PD readout for ATR inhibition that was proportional to drug exposure up to 10 mg/kg and associated with maximal antitumor activity. To date, two small-molecule ATR inhibitors have been reported in the literature (13)(14)(15); however, little is known about the requirements of ATR target engagement and PD-efficacy relationships. Using the GRANTA-519 model, the following parameters were considered: the extent and duration of the pDNA-PKcs PD response, and ATRi PK.…”

Section: Discussionmentioning

confidence: 99%

“…Replication stress, in the absence of ATR can result in unrepaired stalled forks that will collapse into DSBs and eventually lead to cell death. There are several synthetic lethalityinducing agents currently targeting the ATR-CHK1 pathway with promising preclinical and/or clinical trial results (13)(14)(15)(16). To date, two small-molecule ATR inhibitors have been reported in the literature (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

“…It has been established that ATR inhibition exhibits a synthetically lethal interaction in cells with ATM deficiency (13)(14)(15). Here, we identified several other genes in the replication checkpoint, in addition to ATM, that are synthetically lethal with a small molecular weight ATR inhibitor (ATRi).…”

Section: Introductionmentioning

confidence: 99%

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A Synthetic Lethal Screen Reveals Enhanced Sensitivity to ATR Inhibitor Treatment in Mantle Cell Lymphoma with ATM Loss-of-Function

Menezes

Holt

Tang

et al. 2015

Molecular Cancer Research

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Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response pathway factors, such as ataxia telangiectasiamutated (ATM)/ataxia telangiectasia and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content g-H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break (DSB) repair and rely on compensatory repair pathways for survival. Therefore, impairing ATR activity may selectively sensitize cancer cells to killing. ATR inhibition in an ATM-deficient context results in phosphorylation of DNA-dependent protein kinase catalytic subunits (DNAPKcs) and leads to induction of g-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-offunction mantle cell lymphoma (MCL) compared with ATM wildtype cancer cells. In summary, single-agent ATR inhibitors have therapeutic utility in the treatment of cancers, like MCL, in which ATM function has been lost.Implications: These data suggest that single-agent ATR inhibitors have therapeutic utility and that ATR uses a complex and coordinated set of proteins to maintain genomic stability that could be further exploited.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Synthetic Lethal Screen Reveals Enhanced Sensitivity to ATR Inhibitor Treatment in Mantle Cell Lymphoma with ATM Loss-of-Function

Menezes

Holt

Tang

et al. 2015

Molecular Cancer Research

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“…Selective ATR inhibitors only started to emerge in 2011 and were derived by independent strategies [81,[86][87][88]. In our case, we employed a screening based on a cellular model of "at will" ATR activation upon the addition of an inert derivative of tamoxifen [81].…”

Section: Targeting Rs In Cancer Treatmentmentioning

confidence: 99%

“…Promising results with ATR inhibitors in vivo are also starting to emerge. For instance, these compounds limit the growth of colon cancer xenograft models with high basal levels of RS [86]. It should be noted that a recent work has identified that ATR is also essential for the activation of a checkpoint that responds to mechanical and osmotic stress, and which coordinates chromatin condensation with the breakdown of the nuclear envelope [94].…”

Section: Targeting Rs In Cancer Treatmentmentioning

confidence: 99%

Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

119

107

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Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

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Sodium Dithionite‐Mediated Decarboxylative Sulfonylation: Facile Access to Tertiary Sulfones

Chen

Wang

et al. 2020

Angewandte Chemie

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A straightforward multicomponent decarboxylative cross coupling of redox‐active esters (N‐hydroxyphthalimide ester), sodium dithionite, and electrophiles was established to construct sterically bulky sulfones. The inorganic salt sodium dithionite not only served as the sulfur dioxide source, but also acted as an efficient radical initiator for the decarboxylation. Notably, diverse naturally abundant carboxylic acids and artificially prepared carboxyl‐containing drugs with multiple heteroatoms and sensitive functional groups successfully underwent this decarboxylative sulfonylation to provide sterically bulky tertiary sulfones. Mechanistic studies further demonstrated that decarboxylation was the rate‐determining step and occurred via a single‐electron transfer (SET) process with the assistance of sodium dithionite.

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Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity

Cited by 196 publications

References 40 publications

A Synthetic Lethal Screen Reveals Enhanced Sensitivity to ATR Inhibitor Treatment in Mantle Cell Lymphoma with ATM Loss-of-Function

A Synthetic Lethal Screen Reveals Enhanced Sensitivity to ATR Inhibitor Treatment in Mantle Cell Lymphoma with ATM Loss-of-Function

Replication stress and cancer: It takes two to tango

Sodium Dithionite‐Mediated Decarboxylative Sulfonylation: Facile Access to Tertiary Sulfones

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