Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase

Degorce, Sébastien L.; Barlaam, Bernard; Cadogan, Elaine; Dishington, Allan; Ducray, Richard; Glossop, Steven C.; Hassall, Lorraine; Lach, Franck; Lau, Alan; McGuire, Thomas M.; Nowak, Thorsten; Ouvry, Gilles; Pike, Kurt G.; Thomason, Andrew G.

doi:10.1021/acs.jmedchem.6b00519

Cited by 65 publications

(64 citation statements)

References 23 publications

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“…For example, ATM kinase-inactivating mutations lead to embryonic lethality in mice, whereas ATM knockout mice are viable and show less genome instability than kinase-dead mutants (38, 39). To determine the effects of ATM inhibition on MLL-leukemia, we used the newly developed ATM inhibitor AZD0156 (ATMi hereafter) (40) (Fig. 4B).…”

Section: Resultsmentioning

confidence: 99%

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL -rearranged AML

et al. 2016

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Among the various subtypes of Acute Myeloid Leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies due to an attenuated response by p53, which induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AMLMLL cells (with an MLL-ENL fusion and a constitutively active N-RAS) independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AMLMLL and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AMLMLL mice. Collectively, these data indicated that ATR and ATM inhibition represent potential alternative therapeutic strategies for the treatment of AML, especially MLL-driven leukemias.

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Section: Resultsmentioning

confidence: 99%

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL -rearranged AML

et al. 2016

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“…ATR kinase also has a role in bypassing the requirement for BRCA1 for HDR in PARPi-resistant cells by promoting RAD51 recruitment to damage sites (Yazinski et al 2017). Given the use of bioavailable inhibitors of ATM or ATR in combination with genotoxic therapies in mouse tumor models (Degorce et al 2016; Fokas et al 2012; Vendetti et al 2015, 2017), we envision the potential of combining PARPi with ATM/ATR kinase inhibitors in the treatment of BRCA1-deficient tumors.…”

Section: Mechanisms Of Resistance To Poly(adp-ribose) Polymerase Imentioning

confidence: 99%

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

Chen

Feng

Lim

et al. 2018

Annu. Rev. Cancer Biol.

263

221

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Germ-line and somatic mutations in genes that promote homology-directed repair (HDR), especially BRCA1 and BRCA2, are frequently observed in several cancers, in particular, breast and ovary but also prostate and other cancers. HDR is critical for the error-free repair of DNA double-strand breaks and other lesions, and HDR factors also protect stalled replication forks. As a result, loss of BRCA1 or BRCA2 poses significant risks to genome integrity, leading not only to cancer predisposition but also to sensitivity to DNA-damaging agents, affecting therapeutic approaches. Here we review recent advances in our understanding of BRCA1 and BRCA2, including how they genetically interact with other repair factors, how they protect stalled replication forks, how they affect the response to aldehydes, and how loss of their functions links to mutation signatures. Importantly, given the recent advances with poly(ADP-ribose) polymerase inhibitors (PARPi) for the treatment of HDR-deficient tumors, we discuss mechanisms by which BRCA-deficient tumors acquire resistance to PARPi and other agents.

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“…AZ31 is the first selective orally active and bioavailable ATM kinase inhibitor [32]. The ATR kinase inhibitor AZD6738 is also orally active and has been taken into clinical development (ClinicalTrials.gov Identifier: NCT02223923; NCT02630199; NCT01955668; NCT02264678).…”

Section: Introductionmentioning

confidence: 99%

LC–MS/MS assay for the simultaneous quantitation of the ATM inhibitor AZ31 and the ATR inhibitor AZD6738 in mouse plasma

Kiesel

Shogan

Rachid

et al. 2017

Journal of Pharmaceutical and Biomedical Analysis

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The ATM kinase inhibitor AZ31 and ATR kinase inhibitor AZD6738 are in various phases of preclinical and clinical evaluation for their ability to potentiate chemoradiation. To support the preclinical evaluation of their pharmacokinetics, we developed and validated an LC-MS/MS assay for the simultaneous quantification of AZ31 and AZD6738 in mouse plasma. A “dilute and shoot” method was used to precipitate proteins from a sample volume of 50 μL. Chromatographic separation was achieved using a Phenomenex Polar-RP column and a gradient mobile phase consisting of methanol-water with 0.1% formic acid. Detection was accomplished using a Waters Quattro Micro mass spectrometer in positive ionization mode. The assay utilizing 50 μL sample was linear from 10–5,000 ng/mL and determined to be both accurate (−8.2 to 8.6%) and precise (<5.4% CV) and achieved the criteria for U.S. FDA guidance for bioanalytical method validation. Quantification was achieved in mouse tissue homogenate using a separate 200 μL sample preparation. This LC-MS/MS assay will be essential for determining the tissue distribution and pharmacokinetics in future mouse studies.

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Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase

Cited by 65 publications

References 23 publications

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL -rearranged AML

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL -rearranged AML

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

LC–MS/MS assay for the simultaneous quantitation of the ATM inhibitor AZ31 and the ATR inhibitor AZD6738 in mouse plasma

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