The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one)

Pike, Kurt G.; Barlaam, Bernard; Cadogan, Elaine; Campbell, Andrew D.; Chen, Yingxue; Colclough, Nicola; Davies, Nichola L.; de-Almeida, Camila; Degorce, Sébastien L.; Didelot, Myriam; Dishington, Allan; Ducray, Richard; Durant, Stephen T.; Hassall, Lorraine; Holmes, J. L.; Hughes, Gareth; MacFaul, Philip A.; Mulholland, Keith R.; McGuire, Thomas M.; Ouvry, Gilles; Pass, Martin; Robb, Graeme R.; Stratton, Natalie; Wang, Zhenhua; Wilson, Joanne; Zhai, Beibei; Zhao, Kang; Al‐Huniti, Nidal

doi:10.1021/acs.jmedchem.7b01896

Cited by 90 publications

(99 citation statements)

References 59 publications

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“…Similar results were obtained using structurally different inhibitors of ATR and ATM to rule out off-target or nonspecific effects from using a single set of DDR inhibitors ( Fig. 3J and K) (25,26). These findings suggest that activation of both ATR and ATM is required synergistically to prevent progression from S phase during BKPyV infection ( Fig.…”

supporting

confidence: 74%

BK Polyomavirus Activates the DNA Damage Response To Prolong S Phase

Justice

Needham

Thompson

2019

J Virol

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BK polyomavirus (PyV) is a major source of kidney failure in transplant recipients. The standard treatment for patients with lytic BKPyV infection is to reduce immunosuppressive therapy, which increases the risk of graft rejection. PyVs are DNA viruses that rely upon host replication proteins for viral genome replication. A hallmark of PyV infection is activation of the DNA damage response (DDR) to prevent severe host and viral DNA damage that impairs viral production by an unknown mechanism. Therefore, we sought to better understand why BKPyV activates the DDR through the ATR and ATM pathways and how this prevents DNA damage and leads to increased viral production. When ATR was inhibited in BKPyV-infected primary kidney cells, severe DNA damage occurred due to premature Cdk1 activation, which resulted in mitosis of cells that were actively replicating host DNA in S phase. Conversely, ATM was required for efficient entry into S phase and to prevent normal mitotic entry after G 2 phase. The synergistic activation of these DDR kinases promoted and maintained BKPyV-mediated S phase to enhance viral production. In contrast to BKPyV infection, DDR inhibition did not disrupt cell cycle control in uninfected cells. This suggests that DDR inhibitors may be used to specifically target BKPyV-infected cells. IMPORTANCE BK polyomavirus (BKPyV) is an emerging pathogen that reactivates in immunosuppressed organ transplant patients. We wanted to understand why BKPyV-induced activation of the DNA damage response (DDR) enhances viral titers and prevents host DNA damage. Here, we show that the virus activates the DNA damage response in order to keep the infected cells in S phase to replicate the viral DNA. The source of DNA damage was due to actively replicating cells with uncondensed chromosomes entering directly into mitosis when the DDR was inhibited in BKPyV-infected cells. This study clarifies the previously enigmatic role of the DDR during BKPyV infection by demonstrating that the virus activates the DDR to maintain the cells in S phase in order to promote viral replication and that disruption of this cell cycle arrest can lead to catastrophic DNA damage for the host.

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supporting

confidence: 74%

BK Polyomavirus Activates the DNA Damage Response To Prolong S Phase

Justice

Needham

Thompson

2019

J Virol

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“…This novel aspect of EVI1 function, in particular with respect to transformation and self-renewal, is therapeutically relevant for EVI1-overexpressing malignancies, as chemotherapy induced genotoxicity might detrimentally sustain EVI1 function. Inhibition of ATM with an orally applicable compound (51) is currently subject to phase 1 clinical evaluation and has shown activity in a murine leukaemia model (52). ATM inhibition or therapeutic interference of the enhanced EVI1 interaction with CtBP1 after genotoxic stress might be of particular benefit in EVI1 overexpressing malignancies, and this will be subject to further work.…”

Section: Discussionmentioning

confidence: 99%

EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association

Paredes

Schneider

Stevens

et al. 2018

Nucleic Acids Research

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The transcriptional regulator EVI1 has an essential role in early hematopoiesis and development. However, aberrantly high expression of EVI1 has potent oncogenic properties and confers poor prognosis and chemo-resistance in leukemia and solid tumors. To investigate to what extent EVI1 function might be regulated by post-translational modifications we carried out mass spectrometry- and antibody-based analyses and uncovered an ATM-mediated double phosphorylation of EVI1 at the carboxy-terminal S858/S860 SQS motif. In the presence of genotoxic stress EVI1-WT (SQS), but not site mutated EVI1-AQA was able to maintain transcriptional patterns and transformation potency, while under standard conditions carboxy-terminal mutation had no effect. Maintenance of hematopoietic progenitor cell clonogenic potential was profoundly impaired with EVI1-AQA compared with EVI1-WT, in particular in the presence of genotoxic stress. Exploring mechanistic events underlying these observations, we showed that after genotoxic stress EVI1-WT, but not EVI1-AQA increased its level of association with its functionally essential interaction partner CtBP1, implying a role for ATM in regulating EVI1 protein interactions via phosphorylation. This aspect of EVI1 regulation is therapeutically relevant, as chemotherapy-induced genotoxicity might detrimentally sustain EVI1 function via stress response mediated phosphorylation, and ATM-inhibition might be of specific targeted benefit in EVI1-overexpressing malignancies.

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“…AZD0156 was discovered after chemical optimization of a novel series of ATM inhibitors resulting in a highly significant increase in both potency and selectivity, while also delivering a compound with good physicochemical properties, good preclinical pharmacokinetic profiles, and an acceptable predicted clinically efficacious dose (ref. 21; Fig. 1C).…”

Section: Introductionmentioning

confidence: 91%

“…Compounds (AZD0156 and olaparib) were synthesized internally at AstraZeneca laboratories (21) and dissolved in 100% DMSO at 1 mmol/L (AZD0156) or 10 mmol/L (olaparib) stocks, which were used for in vitro studies.…”

Section: Compounds/chemicalsmentioning

confidence: 99%

“…17,18). The activity of PARP inhibitors in BRCAmut tumors exploits the principle of synthetic lethality (19), and preclinical studies indicate that PARP synthetic lethal interactions extend beyond BRCA to DDR proteins including ATM (20)(21)(22). Consequently, inhibition of ATM is anticipated to potentiate the effects of PARP inhibitors in the clinic.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically

Riches

Trinidad

Hughes

et al. 2020

Molecular Cancer Therapeutics

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117

107

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AZD0156 is a potent and selective, bioavailable inhibitor of ataxia-telangiectasia mutated (ATM) protein, a signaling kinase involved in the DNA damage response. We present preclinical data demonstrating abrogation of irradiation-induced ATM signaling by low doses of AZD0156, as measured by phosphorylation of ATM substrates. AZD0156 is a strong radiosensitizer in vitro, and using a lung xenograft model, we show that systemic delivery of AZD0156 enhances the tumor growth inhibitory effects of radiation treatment in vivo. Because ATM deficiency contributes to PARP inhibitor sensitivity, preclinically, we evaluated the effect of combining AZD0156 with the PARP inhibitor olaparib. Using ATM isogenic FaDu cells, we demonstrate that AZD0156 impedes the repair of olaparib-induced DNA damage, resulting in elevated DNA double-strand break signaling, cellcycle arrest, and apoptosis. Preclinically, AZD0156 potentiated the effects of olaparib across a panel of lung, gastric, and breast cancer cell lines in vitro, and improved the efficacy of olaparib in two patient-derived triple-negative breast cancer xenograft models. AZD0156 is currently being evaluated in phase I studies (NCT02588105).

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The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one)

Cited by 90 publications

References 59 publications

BK Polyomavirus Activates the DNA Damage Response To Prolong S Phase

BK Polyomavirus Activates the DNA Damage Response To Prolong S Phase

EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association

Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically

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