The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Discovery of 4-{4-[(3 R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1 H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity
Open accessAbstract
ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.
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A quantitative analysis of kinase inhibitor selectivity
Karaman, M. W., Herrgard, S., Treiber, D. K., Gallant, P., Atteridge, C. E., Campbell, B. T., Chan, K. W., Ciceri, P., Davis, M. I., Edeen, P. T., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt1358 · Cited by 2,466
ATR: an essential regulator of genome integrity
Cimprich, K. A., & Cortez, D. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2450 · Cited by 1,798
Hickson, I., Zhao, Y., Richardson, C. J., Green, S. J., Martin, N. M. B., Orr, A. I., Reaper, P. M., Jackson, S. P., Curtin, N. J., & Smith, G. C. M. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-2727 · Cited by 1,220
Self-citationATR and ATRIP: Partners in Checkpoint Signaling
Cortez, D., Guntuku, S., Qin, J., & Elledge, S. J. (2001) · Science · doi:10.1126/science.1065521 · Cited by 985
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Cited by
Mäder, P., & Kattner, L. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00960 · Cited by 438
Molecular photoswitches in aqueous environments
Volarić, J., Szymanski, W., Simeth, N. A., & Feringa, B. L. (2021) · Chemical Society Reviews · doi:10.1039/d0cs00547a · Cited by 438
ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A
Williamson, C. T., Miller, R., Pemberton, H. N., Jones, S. E., Campbell, J., Konde, A., Badham, N., Rafiq, R., Brough, R., Gulati, A., et al. (2016) · Nature Communications · doi:10.1038/ncomms13837 · Cited by 382
DNA Repair Pathways in Cancer Therapy and Resistance
Li, L.-Y., Guan, Y.-D., Chen, X.-S., Yang, J.-M., & Cheng, Y. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.629266 · Cited by 383
Lecona, E., & Fernandez-Capetillo, O. (2018) · Nature Reviews Cancer · doi:10.1038/s41568-018-0034-3 · Cited by 325
Metadata
- Authors
- Foote, K. M., Blades, K., Cronin, A., Fillery, S., Guichard, S. S., Hassall, L., Hickson, I., Jacq, X., Jewsbury, P. J., McGuire, T. M., Nissink, J. W. M., Odedra, R., Page, K., Perkins, P., Suleman, A., Tam, K., Thommes, P., Broadhurst, R., & Wood, C.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-03-01
- Volume
- 56
- Issue
- 5
- Pages
- 2125-2138
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2330335659
- Cited by
- 214
- References
- 7
- FWCI
- 8.74
- Type
- journal article
- Language
- en
- Open access
- green
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- CoChat. (2026). Citation check: Discovery of 4-{4-[(3 R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1 H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity. https://app.cochat.ai/papers/10.1021/jm301859s
- The paper
- Foote, K. M., Blades, K., Cronin, A., Fillery, S., Guichard, S. S., Hassall, L., Hickson, I., Jacq, X., Jewsbury, P. J., McGuire, T. M., Nissink, J. W. M., Odedra, R., Page, K., Perkins, P., Suleman, A., Tam, K., Thommes, P., Broadhurst, R., & Wood, C. (2013). Discovery of 4-{4-[(3 R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1 H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm301859s
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