Fragment-Based Screening Maps Inhibitor Interactions in the ATP-Binding Site of Checkpoint Kinase 2
Open accessAbstract
Checkpoint kinase 2 (CHK2) is an important serine/threonine kinase in the cellular response to DNA damage. A fragment-based screening campaign using a combination of a high-concentration AlphaScreen™ kinase assay and a biophysical thermal shift assay, followed by X-ray crystallography, identified a number of chemically different ligand-efficient CHK2 hinge-binding scaffolds that have not been exploited in known CHK2 inhibitors. In addition, it showed that the use of these orthogonal techniques allowed efficient discrimination between genuine hit matter and false positives from each individual assay technology. Furthermore, the CHK2 crystal structures with a quinoxaline-based fragment and its follow-up compound highlight a hydrophobic area above the hinge region not previously explored in rational CHK2 inhibitor design, but which might be exploited to enhance both potency and selectivity of CHK2 inhibitors.
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ResultExperiences in Fragment-Based Lead Discovery
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“To date, several ATP-competitive CHK2 inhibitors have been discovered including the guanylhydrazones such as PV1019 (1) [17,27], the isothiazole carboxamidines exemplified by VRX0466617 (2) [22,28], an indoloazepine derivative of hymenialdisine (4) [29,30] and the 2-arylbenzimidazole-5-carboxamides (5) [21,31] (Figure…”
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“inhibition of CHK2 could have the potential to exert an anticancer effect through disruption of DNA-repair pathways pivotal for the survival of cancer cells with high levels of activated CHK2 [1,4,16].”
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“biochemical screening versus NMR [51], NMR versus SPR [62], and SPR versus a high-concentration mobility shift assay [63] revealed a varying degree of correlation between hits discovered”
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“(B) Superposition of compound 20 (light-blue) and the spleen tyrosine kinase inhibitor 24 (pink, PDB ID code 3FQH) [58] showing they bind in a similar way to the hinge gatekeeper +3 residue.”
BackgroundAutophosphorylation of Checkpoint Kinase 2 at Serine 516 Is Required for Radiation-induced Apoptosis
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“In response to double strand DNA breaks, CHK2 is activated through initial phosphorylation on Thr68 by the DNA damage sensor ataxia-telangiectasia mutated (ATM) [5,6] and subsequent trans-autophosphorylation on Thr383 and Thr387 and cis-autophosphorylation on Ser516 [7,8,9,10].”
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“In addition, several dual checkpoint kinase 1 (CHK1)/CHK2 inhibitors with a high affinity for CHK2 have been reported, such as the staurosporine analogue UCN-01 (6) [32,33], the thiophene-2-carboxamide AZD7762 (7) [34,35], the N-(1H-pyrazol-5-yl)pyrazin-2-amine LY2606368 (8) [36,37], the 1H- [1,2]diazepino[4,5,6-cd]in…”
BackgroundCaldwell, J., Welsh, E. J., Matijssen, C., Anderson, V. E., Antoni, L., Boxall, K. J., Urban, F., Hayes, A., Raynaud, F. I., Rigoreau, L. J. M., et al. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm101150b · Cited by 48 · see citing works
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“However, fragment screening using high-concentration biochemical assays is increasingly being employed [45,46,47].”
MethodIdentification of Inhibitors of Checkpoint Kinase 1 through Template Screening
Matthews, T. P., Klair, S., Burns, S., Boxall, K. J., Cherry, M., Fisher, M., Westwood, I. M., Walton, M. I., McHardy, T., Cheung, K.-M. J., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm900314j · Cited by 42 · cited 8× · see citing works
“In addition, several dual checkpoint kinase 1 (CHK1)/CHK2 inhibitors with a high affinity for CHK2 have been reported, such as the staurosporine analogue UCN-01 (6) [32,33], the thiophene-2-carboxamide AZD7762 (7) [34,35], the N-(1H-pyrazol-5-yl)pyrazin-2-amine LY2606368 (8) [36,37], the 1H- [1,2]diazepino[4,5,6-cd]in…”
BackgroundMethodResultInfluentialSelf-citationIdentification of novel, selective and potent Chk2 inhibitors
Larson, G., Yan, S., Chen, H., Rong, F., Hong, Z., & Wu, J. Z. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.09.067 · Cited by 41 · cited 1× · see citing works
“To date, several ATP-competitive CHK2 inhibitors have been discovered including the guanylhydrazones such as PV1019 (1) [17,27], the isothiazole carboxamidines exemplified by VRX0466617 (2) [22,28], an indoloazepine derivative of hymenialdisine (4) [29,30] and the 2-arylbenzimidazole-5-carboxamides (5) [21,31] (Figure…”
BackgroundOrita, M., Ohno, K., Warizaya, M., Amano, Y., & Niimi, T. (2011) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-381274-2.00015-7 · Cited by 40 · cited 2× · see citing works
“Furthermore, in keeping with the majority of advanced fragment-based kinase inhibitors, such as the B-raf inhibitor PLX4032 (Vemurafenib) [66], the PKB/Akt inhibitor AZD5363 [67], and the Aurora Janus kinase 2 inhibitor AT9283 [68], optimization using a fragment evolution/growing strategy [64] would be the most promis…”
BackgroundLeoprechting, A. V., Kumpf, R., Menzel, S., Reulle, D., Griebel, R., Valler, M. J., & Büttner, F. H. (2004) · SLAS DISCOVERY · doi:10.1177/1087057104268805 · Cited by 39 · cited 1× · see citing works
“Full-length CHK2 was screened against the ICR fragment library consisting of 1869 fragments using a biochemical assay based on AlphaScreen technology [71] in which the CHK2 kinase activity was measured by monitoring the phosphorylation of a CDC25C peptide using a phospho-specific antibody [40].”
MethodA comparative study of fragment screening methods on the p38α kinase: new methods, new insights
Pollack, S. J., Beyer, K. S., Lock, C., Müller, I., Sheppard, D. W., Lipkin, M., HARDICK, D. J., Blurton, P., Leonard, P. M., Hubbard, P. A., et al. (2011) · Journal of Computer-Aided Molecular Design · doi:10.1007/s10822-011-9454-9 · Cited by 34 · see citing works
Neff, D. K., Lee-Dutra, A., Blevitt, J. M., Axe, F. U., Hack, M. D., Buma, J., Rynberg, R., Brunmark, A. B., Karlsson, L., & Breitenbucher, J. G. (2007) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2007.09.098 · Cited by 33 · cited 1× · see citing works
“To date, several ATP-competitive CHK2 inhibitors have been discovered including the guanylhydrazones such as PV1019 (1) [17,27], the isothiazole carboxamidines exemplified by VRX0466617 (2) [22,28], an indoloazepine derivative of hymenialdisine (4) [29,30] and the 2-arylbenzimidazole-5-carboxamides (5) [21,31] (Figure…”
Background4-Phenyl-7-azaindoles as potent and selective IKK2 inhibitors
Liddle, J., Bamborough, P., Barker, M. D., Campos, S., Cousins, R. P. C., Cutler, G. J., Hobbs, H., Holmes, D. S., Ioannou, C., Mellor, G. W., et al. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.03.034 · Cited by 29 · see citing works
Lountos, G. T., Tropea, J. E., Zhang, D., Jobson, A. G., Pommier, Y. G., Shoemaker, R. H., & Waugh, D. S. (2008) · Protein Science · doi:10.1002/pro.16 · Cited by 28 · cited 1× · see citing works
“Intriguingly, although their respective hydroxyl groups occupy the same space, which is also the location of the mediating water molecule in the NSC109555[55] and PV1019-bound [17] structures, the aromatic parts of compound 12 and the phenol-moiety in the 2-(quinazolin-2yl)phenol inhibitors do not superimpose (Figure…”
BackgroundSynthesis and evaluation of debromohymenialdisine-derived Chk2 inhibitors
Saleem, R. S. Z., Lansdell, T. A., & Tepe, J. J. (2012) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2011.12.054 · Cited by 23 · cited 1× · see citing works
“To date, several ATP-competitive CHK2 inhibitors have been discovered including the guanylhydrazones such as PV1019 (1) [17,27], the isothiazole carboxamidines exemplified by VRX0466617 (2) [22,28], an indoloazepine derivative of hymenialdisine (4) [29,30] and the 2-arylbenzimidazole-5-carboxamides (5) [21,31] (Figure…”
BackgroundLountos, G. T., Jobson, A. G., Tropea, J. E., Self, C. R., Zhang, G., Pommier, Y. G., Shoemaker, R. H., & Waugh, D. S. (2011) · Journal of Structural Biology · doi:10.1016/j.jsb.2011.09.008 · Cited by 22 · cited 1× · see citing works
“therapies in patients with this profile [4,20].”
Matijssen, C., Silva-Santisteban, M. C., Westwood, I. M., Siddique, S., Choi, V., Sheldrake, P. W., van Montfort, R. L. M., & Blagg, J. (2012) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2012.09.024 · Cited by 10 · cited 2× · see citing works
“Furthermore, the interaction with the side chain of Thr367 observed with compounds 11 and 14 (water-mediated) and compound 12 (direct) is also found in a series of potent benzimidazole-based CHK2 inhibitors, such as 2-(4-((1-benzylpiperidin-4-yl)methoxy)phenyl)-1H-benzo[d]imidazole-5-carboxamide [56] (5, Figure 5D).”
BackgroundResultSelf-citationWu, W., Chen, B., Bence, A. K., Um, S. L., Yan, B. S., Starling, J. J., Marshall, M. S., & Beckmann, R. P. (2012) · Cancer Research · doi:10.1158/1538-7445.am2012-1776 · Cited by 8 · see citing works
McNeely, S., Burke, T. F., Durland–Busbice, S., Barnard, D., Marshall, M. S., Bence, A. K., & Beckmann, R. P. (2011) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.targ-11-a108 · Cited by 6 · see citing works
Hilton, S. T., Naud, S., Caldwell, J., Boxall, K. J., Burns, S., Anderson, V. E., Antoni, L., Allen, C. E., Pearl, L. H., Oliver, A. W., et al. (2010) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2010.05.014 · Cited by 3 · see citing works
Self-citation
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Cited by
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Modulators of Protein–Protein Interactions
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L., & Ottmann, C. (2014) · Chemical Reviews · doi:10.1021/cr400698c · Cited by 497 · see citing works
Keserű, G. M., Erlanson, D. A., Ferenczy, G. G., Hann, M. M., Murray, C. W., & Pickett, S. D. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00197 · Cited by 244 · see citing works
Structure-based drug design: aiming for a perfect fit
van Montfort, R. L. M., & Workman, P. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170052 · Cited by 127 · see citing works
Firth, N. C., Atrash, B., Brown, N., & Blagg, J. (2015) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5b00073 · Cited by 61 · see citing works
Self-citationPollock, K., Liu, M., Zaleska, M., Meniconi, M., Pfuhl, M. A., Collins, I., & Guettler, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-55240-5 · Cited by 29 · see citing works
Self-citationZhu, Y., Alqahtani, S. M., & Hu, X. (2024) · Molecules · doi:10.3390/molecules29020304 · Cited by 20 · see citing works
Лавренова, Л. Г., Кузьменко, Т. А., Иванова, А. Д., Smolentsev, A. I., Komarov, V. Y., Bogomyakov, A. S., Sheludyakova, L. A., & Воронцова, Е. В. (2017) · New Journal of Chemistry · doi:10.1039/c7nj00533d · Cited by 19 · see citing works
Differential Scanning Fluorimetry as Part of a Biophysical Screening Cascade
Scott, D. E., Spry, C., & Abell, C. (2016) · Methods and principles in medicinal chemistry · doi:10.1002/9783527683604.ch07 · Cited by 17 · see citing works
Acetogenins as potential checkpoint-2 kinase inhibitors: an in silico analysis
Meghana, P., Kumar, J. R. S., Sandeep, T., Prashanth, N., & Kumaraswamy, H. M. (2019) · Journal of Proteins and Proteomics · doi:10.1007/s42485-019-00025-7 · Cited by 6 · see citing works
Bulfer, S. L., Jean-Francois, F. L., & Arkin, M. R. (2016) · Methods and principles in medicinal chemistry · doi:10.1002/9783527683604.ch10 · Cited by 5 · see citing works
Kolpe, M. S., Suryawanshi, V. S., Eldesoky, G. E., Hossain, D., Patil, P. C., & Bhowmick, S. (2024) · ChemistrySelect · doi:10.1002/slct.202403302 · Cited by 3 · see citing works
Koshchienko, Y. V., Кузьменко, Т. А., Морковник, А. С., Kiskin, M. A., & Alexandrov, G. G. (2016) · Mendeleev Communications · doi:10.1016/j.mencom.2016.07.018 · Cited by 3 · see citing works
Komarova, E. F., Морковник, А. С., Zhukovskaya, O. N., Verenikina, E. V., Shevchenko, N. A., Владиславовна, Х. Д., Kurbanova, L. Z., Вадимовна, М. М., Заикина, Е. В., & Galina, A. V. (2022) · South Russian Journal of Cancer · doi:10.37748/2686-9039-2022-3-1-2 · Cited by 3 · see citing works
“Thus, triazolobenzimidazole is able to inhibit check point kinase 2, which plays an important role in the cell's response to DNA damage, and therefore has an antitumor effect [6].”
BackgroundThe hunt for antimitotic agents: an overview of structure-based design strategies
Dubé, D., Tiwari, P., & Kaur, P. (2016) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2016.1174689 · Cited by 3 · see citing works
Using Fragment Based Drug Discovery to Target Epigenetic Regulators in Cancer
Young, D. W. (2017) · MOJ Bioequivalence & Bioavailability · doi:10.15406/mojbb.2017.04.00062 · Cited by 3 · see citing works
Targeting DNA Damage Response Pathways in Cancer
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Different Flavours of Fragments
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Docking Based Screening of Potent Flavonoids as CHK2 Inhibitors from Genus Miliusa
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4-substituted 2-chloromethyl[1,2,4]triazolo[1,5-a]benzimidazoles and their transformations
Кузьменко, Т. А., Диваева, Л. Н., & Морковник, А. С. (2015) · Russian Journal of Organic Chemistry · doi:10.1134/s1070428015100218 · Cited by 1 · see citing works
Комарова, Е. Ф., Жуковская, О. Н., Lukbanova, E. A., Енгибарян, М. А., Позднякова, В. В., Ушакова, Н. Д., Шатова, Ю. С., Пржедецкий, Ю. В., Vashchenko, L. N., & Kharagezov, D. A. (2021) · Вестник Российского государственного медицинского университета · doi:10.24075/vrgmu.2021.031 · Cited by 1 · see citing works
FBDD Applications to Kinase Drug Hunting
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Affinity‐Based Screening Methodologies and Their Application in the Hit‐to‐Lead Phase
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Benzimidazole derivative as antitumor drug against experimentally induced lung carcinoma
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“A total of 1097 compounds from the ICR biophysical fragment library 39 were screened in pools of four structurally dissimilar molecules with non-overlapping resonances in the aromatic region of the 1 H spectrum (5.5–9.5 ppm).”
InfluentialSelf-citationTargeting DNA damage response pathways in cancer
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Fragment-Based Discovery of Potent RNA-Competitive Inhibitors of the DEAH-Box RNA Helicase DHX8
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Self-citationNavyatha, J., Vasanth, S., Sowntharya, P., Amaladass, P., & Dhayalan, V. (2026) · Bulletin of the Korean Chemical Society · doi:10.1002/bkcs.70203
- Authors
- Silva-Santisteban, M. C., Westwood, I. M., Boxall, K., Brown, N., Peacock, S., McAndrew, C., Barrie, E., Richards, M., Mirza, A., Oliver, A. W., Burke, R., Hoelder, S., Jones, K., Aherne, G. W., Blagg, J., Collins, I., Garrett, M. D., & van Montfort, R. L. M.
- Affiliations
- Institute of Cancer Research (GB)
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-06-12
- Volume
- 8
- Issue
- 6
- Pages
- e65689
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3680490
- OpenAlex
- W2096062218
- Cited by
- 31
- References
- 80
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 2 · 2017: 4 · 2016: 7 · 2015: 3 · 2014: 1
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Kent Academic Repository (University of Kent) (submittedVersion)
- Funders
- Wellcome Trust
- Diamond Light Source
- Cancer Research UK (11566, C309/A8274, 14532)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- checkpoint kinase 2, CHK2 inhibitors, ATP binding site, fragment screening, thermal shift assay, DNA damage response, kinase inhibitor design
- MeSH terms
- Adenosine Triphosphate, Binding Sites, Crystallography, Models, Molecular, Protein Conformation, Molecular Structure, Crystallography, X-Ray, Protein Kinase Inhibitors, Checkpoint Kinase 2
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