Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-26T07:06:47.018Z Has data issue: false hasContentIssue false
  • English
  • Français

Chemical strategies for development of ATR inhibitors

Published online by Cambridge University Press:  09 May 2014

Sabin Llona-Minguez ,
Andreas Höglund ,
Sylvain A. Jacques ,
Tobias Koolmeister  and
Thomas Helleday
Sabin Llona-Minguez*
Affiliation:
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
Andreas Höglund
Affiliation:
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
Sylvain A. Jacques
Affiliation:
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
Tobias Koolmeister
Affiliation:
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
Thomas Helleday*
Affiliation:
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden
*
*Corresponding authors: Thomas Helleday and Sabin Llona-Minguez, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden. E-mail: [email protected]; [email protected]
*Corresponding authors: Thomas Helleday and Sabin Llona-Minguez, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden. E-mail: [email protected]; [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

ATR protein kinase is one of the key players in maintaining genome integrity and coordinating of the DNA damage response and repair signalling pathways. Inhibition of ATR prevents signalling from stalled replication forks and enhances the formation of DNA damage, particularly under conditions of replication stress present in cancers. For this reason ATR/CHK1 checkpoint inhibitors can potentiate the effect of DNA cross-linking agents, as evidenced by ATR inhibitors recently entering human clinical trials. This review aims to compile the existing literature on small molecule inhibitors of ATR, both from academia and the pharmaceutical industry, and will provide the reader with a comprehensive summary of this promising oncology target.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 16 , 2014 , e10
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Hoeijmakers, J.H. (2009) DNA damage, aging, and cancer. New England Journal of Medicine 361, 1475-1485CrossRefGoogle ScholarPubMed
2Shiloh, Y. (2003) ATM and related protein kinases: safeguarding genome integrity. Nature Reviews Cancer 3, 155-168CrossRefGoogle ScholarPubMed
3Phillips, D.H. et al. (1988) Correlation of DNA adduct levels in human lung with cigarette smoking. Nature 336, 790-792CrossRefGoogle ScholarPubMed
4Lindahl, T. and Barnes, D.E. (2000) Repair of endogenous DNA damage. Cold Spring Harbor Symposia on Quantitative Biology 65, 127-134CrossRefGoogle ScholarPubMed
5Cortez, D. et al. (2001) ATR and ATRIP: partners in checkpoint signaling. Science 294, 1713-1716CrossRefGoogle ScholarPubMed
6Zou, L. and Elledge, S.J. (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300, 1542-1548CrossRefGoogle ScholarPubMed
7Delacroix, S. et al. (2007) The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1. Genes & Development 21, 1472-1477CrossRefGoogle ScholarPubMed
8Lee, J., Kumagai, A. and Dunphy, W.G. (2007) The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. Journal of Biological Chemistry 282, 28036-28044CrossRefGoogle ScholarPubMed
9Mordes, D.A. et al. (2008) TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes & Development 22, 1478-1489CrossRefGoogle Scholar
10Kondo, T. et al. (2001) Recruitment of Mec1 and Ddc1 checkpoint proteins to double-strand breaks through distinct mechanisms. Science 294, 867-870CrossRefGoogle ScholarPubMed
11Melo, J.A., Cohen, J. and Toczyski, D.P. (2001) Two checkpoint complexes are independently recruited to sites of DNA damage in vivo. Genes & Development 15, 2809-2821CrossRefGoogle ScholarPubMed
12Matsuoka, S. et al. (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 1160-1166CrossRefGoogle ScholarPubMed
13Tibbetts, R.S. et al. (1999) A role for ATR in the DNA damage-induced phosphorylation of p53. Genes & Development 13, 152-157CrossRefGoogle ScholarPubMed
14Dumaz, N. and Meek, D.W. (1999) Serine15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2. EMBO Journal 18, 7002-7010CrossRefGoogle Scholar
15López-Contreras, A.J. and Fernandez-Capetillo, O. (2010) The ATR barrier to replication-born DNA damage. DNA Repair 9, 1249-1255CrossRefGoogle ScholarPubMed
16Fokas, E. et al. (2013) Targeting ATR in DNA damage response and cancer therapeutics. Cancer Treatment Reviews 40, 109-117CrossRefGoogle ScholarPubMed
17Nghiem, P. et al. (2001) ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation. Proceedings of the National Academy of Sciences USA 98, 9092-9097CrossRefGoogle ScholarPubMed
18Dai, Y. and Grant, S. (2010) New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clinical Cancer Research 16, 376-383CrossRefGoogle ScholarPubMed
19Garrett, M.D. and Collins, I. (2011) Anticancer therapy with checkpoint inhibitors: what, where and when? Trends in Pharmacological Sciences 32, 308-316CrossRefGoogle ScholarPubMed
20Chen, C. et al. (2009) CHK1 inhibition as a strategy for targeting fanconi anemia (FA) DNA repair pathway deficient tumors. Molecular Cancer 8, 1-16CrossRefGoogle ScholarPubMed
21Höglund, A. et al. (2011) Therapeutic implications for the induced levels of CHK1 in MYC-expressing cancer cells. Clinical Cancer Research 17, 7067-7079CrossRefGoogle ScholarPubMed
22Cole, K.A. et al. (2011) RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma. Proceedings of the National Academy of Sciences USA 108, 3336-3341CrossRefGoogle ScholarPubMed
23Schoppy, D.W. et al. (2012) Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. The Journal of Clinical Investigation 122, 241-252CrossRefGoogle ScholarPubMed
24http://clinicaltrials.gov/ct2/show/NCT01955668Google Scholar
25https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-003126-25/GBGoogle Scholar
26Vlahos, C.J. et al. (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). Journal of Biological Chemistry 269, 5241-5248CrossRefGoogle ScholarPubMed
27Rosenzweig, K.E. et al. (1997) Radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. Clinical Cancer Research 3, 1149-1156Google ScholarPubMed
28Lee, C.M. et al. (2006) Phosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell lines. Clinical Cancer Research 12, 250-256CrossRefGoogle ScholarPubMed
29Knight, Z.A. et al. (2006) A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell 125, 733-747CrossRefGoogle ScholarPubMed
30Sarkaria, J.N. et al. (1998) Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Research 58, 4375-4382Google ScholarPubMed
31Sarkaria, J.N. et al. (1999) Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, Caffeine. Cancer Research 59, 4375-4382Google ScholarPubMed
32Planelles, V., Roshal, M. and Zhu, Y.H. (2003) Patent WO2003068929A2, University of Rochester, USA; University of UtahGoogle Scholar
33Nghiem, P. and Fujii, S. (2005) Patent US20050276765A1, General Hospital Corporation, USAGoogle Scholar
34Nishida, H., Hamamori, Y. and Konishi, T. (2007) Patent WO2007046426A1, Niigata Tlo Corp., JapanGoogle Scholar
35Nishida, H. et al. (2009) Inhibition of ATR protein kinase activity by schisandrin B in DNA damage response. Nucleic Acids Research 37, 5678-5689CrossRefGoogle ScholarPubMed
36Liu, Q. et al. (2013) Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. Cancer Research 73, 2574-2586CrossRefGoogle ScholarPubMed
37Toledo, L.I. et al. (2011) A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nature Structural & Molecular Biology 18, 721-727CrossRefGoogle ScholarPubMed
38Kumagai, A. et al. (2006) TopBP1 activates the ATR–ATRIP complex. Cell 124, 943–955CrossRefGoogle Scholar
39Toledo, L.I. et al. (2008) ATR signaling can drive cells into senescence in the absence of DNA breaks. Genes & Development 22, 297-302CrossRefGoogle ScholarPubMed
40http://www.merckmillipore.com/life-science-research/ucn-01/EMD_BIO-539644/p_R66b.s1LTrMAAAEWx2EfVhTmGoogle Scholar
41Maira, S.-M. et al. (2008) Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Molecular Cancer Therapeutics 7, 1851-1863CrossRefGoogle ScholarPubMed
42http://clinicaltrials.gov/show/NCT00620594Google Scholar
43Konstantinidou, G. et al. (2009) Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non–small cell lung cancer harboring K-RAS mutations. Cancer Research 69, 7644-7652CrossRefGoogle ScholarPubMed
44Gilad, O. et al. (2010) Combining ATR suppression with oncogenic ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Research 70, 9693-9702CrossRefGoogle ScholarPubMed
45Peasland, A. et al. (2011) Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. British Journal of Cancer 105, 372-381CrossRefGoogle ScholarPubMed
46D'Andrea, A.D. and Taniguchi, T. (2006) Patent WO2006127978A2, Dana Farber Cancer Institute Inc., USAGoogle Scholar
47Andreassen, P.R., D'Andrea, A.D. and Taniguchi, T. (2004) ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes & Development 18, 1958-1963CrossRefGoogle ScholarPubMed
48Ho, G.P.H. et al. (2006) Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance. Molecular and Cellular Biology 26, 7005-7015CrossRefGoogle ScholarPubMed
49Kim, T.K., Won, J.-J. and Yi, Y.-W. (2007) Patent WO2007015632A1, Cgk Co., Ltd., S. KoreaGoogle Scholar
50Won, J. et al. (2006) Small molecule-based reversible reprogramming of cellular lifespan. Nature Chemical Biology 2, 369-374CrossRefGoogle ScholarPubMed
51Won, J. et al. (2008) Retraction: small molecule-based reversible reprogramming of cellular lifespan. Nature Chemical Biology 4, 431–431CrossRefGoogle ScholarPubMed
52Foote, K.M. and Nissink, J.W.M. (2010) Patent WO2010073034A1, Astrazeneca AB, Swed.; Astrazeneca UK LimitedGoogle Scholar
53Foote, K.M., Nissink, J.W.M. and Turner, P. (2011) Patent WO2011154737A1, AstraZeneca AB, Swed.; AstraZeneca UK LimitedGoogle Scholar
54Charrier, J.-D. et al. (2010) Patent WO2010054398A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
55Charrier, J.-D. et al. (2011) Patent WO2011143426A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
56Charrier, J.-D. et al. (2010) Patent WO2010071837A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
57Charrier, J.-D., Durrant, S.J. and Knegtel, R. (2013) Patent WO2013071085A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
58Charrier, J.-D. et al. (2011) Patent WO2011143419A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
59Charrier, J.-D. et al. (2011) Patent WO2011143399A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
60Charrier, J.-D. et al. (2011) Patent WO2011143422A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
61Charrier, J.-D. et al. (2011) Patent WO2011143425A2, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
62Charrier, J.-D., Durrant, S.J. and Shaw, D.M. (2013) Patent WO2013071088A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
63Charrier, J.-D. et al. (2011) Patent WO2011143423A2, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
64Charrier, J.-D. and Kay, D. (2013) Patent WO2013071094A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
65Charrier, J.-D. et al. (2012) Patent WO2012138938A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
66Charrier, J.-D. et al. (2011) Patent WO2011163527A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
67Charrier, J.-D. et al. (2013) Patent WO2013071090A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
68Charrier, J.-D. et al. (2013) Patent WO2013049726A2, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
69Charrier, J.-D. et al. (2013) Patent WO2013049719A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
70Everitt, S. et al. (2012) Patent WO2012178124A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
71MacCormick, S. et al. (2012) Patent WO2012178123A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
72Pollard, J.R. and Reaper, P.M. (2013) Patent WO2013049859A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
73Storck, P.-H. et al. (2012) Patent WO2012178125A1, Vertex Pharmaceuticals Incorporated, USAGoogle Scholar
74Foote, K.M. et al. (2013) 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. Journal of Medicinal Chemistry 56, 2125-2138CrossRefGoogle ScholarPubMed
75Reaper, P.M. et al. (2011) Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nature Chemical Biology 7, 428-430CrossRefGoogle ScholarPubMed
76Charrier, J.-D. et al. (2011) Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. Journal of Medicinal Chemistry 54, 2320-2330CrossRefGoogle ScholarPubMed
77Cao, Y.F. et al. (2010) CYP3A catalyses schizandrin biotransformation in human, minipig and rat liver microsomes. Xenobiotica 40, 38-47CrossRefGoogle ScholarPubMed
78Morphy, R. (2009) Selectively nonselective kinase inhibition: striking the right balance. Journal of Medicinal Chemistry 53, 1413-1437CrossRefGoogle Scholar
79Knight, Z.A., Lin, H. and Shokat, K.M. (2010) Targeting the cancer kinome through polypharmacology. Nature Reviews Cancer 10, 130-137CrossRefGoogle ScholarPubMed
80Dar, A.C. et al. (2012) Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature 486, 80-84CrossRefGoogle ScholarPubMed
81Wagner, J.M. and Kaufmann, S.H. (2010) Prospects for the use of ATR inhibitors to treat cancer. Pharmaceuticals 3, 1311-1334CrossRefGoogle ScholarPubMed