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Targeting the cancer kinome through polypharmacology
Open accessAbstract
Kinase inhibitors are the largest class of new cancer drugs. However, it is already apparent that most tumours can escape from the inhibition of any single kinase. If it is necessary to inhibit multiple kinases, how do we choose which ones? In this Opinion article, we discuss some of the strategies that are currently being used to identify new therapeutic combinations of kinase targets.
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“We found no correlation between these variables, consistent with evidence that kinase inhibitor pharmacophores display a high degree of polypharmacology”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Knight et al., 2010
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“The rationale for targeting multiple pathways is also justified by the resistance that a drug-targeted enzyme could develop to the drug itself through multiple mechanisms, including amino acid mutations, constitutive activation of alternative signaling pathways, and inactivation of phosphatases to amplify the kinase a…”
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“In general, modulating the immune system by small compounds may be a desirable integrated positive effect that is more common than previously expected, and a result of their full polypharmacological properties 49,50.”
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“For example, FDA approved kinase inhibitors often have binding affinities with multiple kinases harbouring similar ATP binding pockets, which have demonstrated their high efficiency for targeted cancer therapies in clinical practice (Knight et al., 2010).”
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“…partners can confer resistance to ATP-analog inhibitors, which provides an explanation for why kinases, such as Akt (PKB) and B-Raf, can become refractory to certain anticancer drugs (Brennan et al., 2011; Knight et al., 2010; Okuzumi et al., 2010; Okuzumi et al., 2009; Poulikakos et al., 2010).”
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“For these conditions, in most cases, KIs have led to multiyear increases in survival (39).”
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Cross-resistance to clinically used tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib
Gotink, K. J., Rovithi, M. N., de Haas, R. R., Honeywell, R. J., Dekker, H., Poel, D., Azijli, K., Peters, G. J., Broxterman, H. J., & Verheul, H. M. W. (2015) · Cellular Oncology · doi:10.1007/s13402-015-0218-8 · Cited by 59
“primary RCCs or in RCC-derived cell lines that would constitute indisputable proof that this mutated kinase is required for tumor growth and/or survival [17].”
BackgroundKinome-wide Activity Modeling from Diverse Public High-Quality Data Sets
Schürer, S. C., & Muskal, S. M. (2012) · Journal of Chemical Information and Modeling · doi:10.1021/ci300403k · Cited by 58
Allen, B. K., Mehta, S., Ember, S. W. J., Schönbrunn, E., Ayad, N. G., & Schürer, S. C. (2015) · Scientific Reports · doi:10.1038/srep16924 · Cited by 61
Docking Screens for Dual Inhibitors of Disparate Drug Targets for Parkinson’s Disease
Jaiteh, M., Zeifman, A. A., Saarinen, M., Svenningsson, P., Brea, J. M., Loza, M. I., & Carlsson, J. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00204 · Cited by 61
“The idea of developing dual-target A 2A AR/MAO-B inhibitors emerged from the serendipitous discovery that the A 2A antagonist 8-(3-chlorostyryl)ca ff eine (CSC) also inhibited MAO-B.”
Selective killing of p53‐deficient cancer cells by SP600125
Jèmaà, M., Vitale, I., Kepp, O., Berardinelli, F., Galluzzi, L., Senovilla, L., Mariño, G., Malik, S. A., Rello‐Varona, S., Lissa, D., et al. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201200228 · Cited by 60
“…the simultaneous inhibition of several kinases may exert synergistic pro-apoptotic actions (Olaussen et al, 2009) and that less specific kinase inhibitors may have broader anticancer effects than highly targeted agents, as this has been determined in several clinical studies (Knight et al, 2010).”
The Energy Landscape Analysis of Cancer Mutations in Protein Kinases
Dixit, A., & Verkhivker, G. M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026071 · Cited by 56
“Structural studies of protein kinase catalytic domain structures and regulatory protein complexes have revealed distinct scenarios by which kinases can control a dynamic equilibrium between structurally similar active and highly specific inactive kinase states - a structural hallmark of the kinase domain critical for…”
A Multilayer Network Approach for Guiding Drug Repositioning in Neglected Diseases
Berenstein, A. J., Magariños, M. P., Chernomoretz, A., & Agüero, F. (2016) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0004300 · Cited by 58
“Apart from also being a rich source of highly druggable targets, from the point of view of the network this is a protein class with strong ties (abundant or heavy edges) between family members (both because of orthology and shared Pfam domains), and with abundant bioactivity links (EDP edges) due to the recognized tar…”
BackgroundSecondary pharmacology: screening and interpretation of off-target activities – focus on translation
Whitebread, S., Dumotier, B. M., Armstrong, D., Fekete, A., Chen, S., Hartmann, A., Muller, P. Y., & Urbán, L. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.04.021 · Cited by 59
Christmann‐Franck, S., van Westen, G. J. P., Papadatos, G., Escudie, F. B., Roberts, A., Overington, J. P., & Domine, D. (2016) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.6b00122 · Cited by 55
Impairing Powerhouse in Colon Cancer Cells by Hydrazide–Hydrazone-Based Small Molecule
Patil, S., Kuman, M. M., Palvai, S., Sengupta, P., & Basu, S. (2018) · ACS Omega · doi:10.1021/acsomega.7b01512 · Cited by 55
Ling, Y., Liu, J., Qian, J., Meng, C., Guo, J., Gao, W., Xiong, B., Ling, C., & Zhang, Y. (2020) · Current Medicinal Chemistry · doi:10.2174/0929867327666200102115720 · Cited by 57
Cheng, F., Zhao, J., Fooksa, M., & Zhao, Z. (2016) · Journal of the American Medical Informatics Association · doi:10.1093/jamia/ocw007 · Cited by 57
“, kinase inhibitors).(47) In addition, we found that several SMGs (such as TLR4 and SCN9A) can potentially be targeted by FDA-approved noncancer drugs.”
BackgroundA Structural Atlas of Kinases Inhibited by Clinically Approved Drugs
Wang, Q., Zorn, J. A., & Kuriyan, J. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-397918-6.00002-1 · Cited by 56
Zheng, M., Zhao, J., Cui, C., Fu, Z., Li, X., Liu, X., Ding, X., Tan, X., Li, F., Luo, X., et al. (2018) · Medicinal Research Reviews · doi:10.1002/med.21483 · Cited by 55
Kim, S., Kim, W., Kim, D., Jang, J., Kim, S., Park, S., Hahn, H., Han, B. W., Na, H., Chun, K., et al. (2020) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2020.108413 · Cited by 54
Decoding the messaging of the ubiquitin system using chemical and protein probes
Henneberg, L. T., & Schulman, B. A. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.03.009 · Cited by 53
“As examples, small molecule inhibitors of kinases, histone acetyltransferases, and histone-deacetylases have revolutionized our understanding of phospho and acetyl regulation (Dokmanovic and Marks, 2005; Knight et al., 2010; Zhang et al., 2009).”
BackgroundTarget deconvolution of bioactive small molecules: the heart of chemical biology and drug discovery
Jung, H. J., & Kwon, H. J. (2015) · Archives of Pharmacal Research · doi:10.1007/s12272-015-0618-3 · Cited by 55
“context, poly-pharmacology or pan-pharmacology, or the action of drugs against multiple targets, is emerging as the next paradigm of drug discovery (Wermuth 2004; Knight et al. 2010; Masoudi-Nejad et al. 2013).”
BackgroundDhakal, H. P., Naume, B., Synnestvedt, M., Borgen, E., Kaaresen, R., Schlichting, E., Wiedswang, G., Bassarova, A. V., Holm, R., Giercksky, K.-E., et al. (2012) · Histopathology · doi:10.1111/j.1365-2559.2012.04223.x · Cited by 52
“The use of tyrosine kinase-inhibiting drugs such as sunitinib, which also target VEGFRs, are used in kidney cancer.(45) Humanized monoclonal antibodies targeting VEGFR-2 may be useful in treating breast cancer.”
BackgroundCarlino, L., & Rastelli, G. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00438 · Cited by 52
High-resolution view of compound promiscuity
Hu, Y., & Bajorath, J. (2013) · F1000Research · doi:10.12688/f1000research.2-144.v2 · Cited by 51
Dort, M. E. V., Hong, H., Wang, H., Nino, C. A., Lombardi, R. L., Blanks, A., Galbán, S., & Ross, B. D. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01655 · Cited by 51
EXPLORING COMPOUND PROMISCUITY PATTERNS AND MULTI-TARGET ACTIVITY SPACES
Hu, Y., Gupta‐Ostermann, D., & Bajorath, J. (2014) · Computational and Structural Biotechnology Journal · doi:10.5936/csbj.201401003 · Cited by 51
Niijima, S., Shiraishi, A., & Okuno, Y. (2012) · Journal of Chemical Information and Modeling · doi:10.1021/ci200607f · Cited by 49
A Genetically Encoded 19 F NMR Probe for Tyrosine Phosphorylation
Li, F., Shi, P., Li, J., Yang, F., Wang, T., Zhang, W., Gao, F., Ding, W., Li, D., Li, J., et al. (2013) · Angewandte Chemie International Edition · doi:10.1002/anie.201300463 · Cited by 50
Daydé-Cazals, B., Fauvel, B., Singer, M., Feneyrolles, C., Bestgen, B., Gassiot, F., Spenlinhauer, A., Warnault, P., Hijfte, N. V., Borjini, N., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00087 · Cited by 50
SRC Kinase in Glioblastoma: News from an Old Acquaintance
Cirotti, C., Contadini, C., & Barilà, D. (2020) · Cancers · doi:10.3390/cancers12061558 · Cited by 49
“The majority of SRC tyrosine kinase inhibitors (STKIs) binds to the kinase adenosine triphosphate (ATP) pocket, which is conserved among kinases, thus, representing a potential cause of cross-reactivity [97].”
BackgroundRecently targeted kinases and their inhibitors—the path to clinical trials
Knapp, S., & Sundström, M. (2014) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2014.07.015 · Cited by 50
“Thus, the kinase inhibitor development efforts have to a large extent shifted from the dogma in the 1990s with one molecule, one target one disease; to attempts towards controlled multi-targeting to address the genetic diversity and multiple driving forces of disease, or towards indications with more dominant driving…”
BackgroundDort, M. E. V., Galbán, S., Wang, H., Sebolt, J. S., Whitehead, C. E., Hong, H., Rehemtulla, A., & Ross, B. D. (2015) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2015.02.053 · Cited by 49
“The pros and cons of each approach have been recently reviewed [23].”
BackgroundPetri, L., Egyed, A., Bajusz, D., Imre, T., Hetényi, A., Martinek, T. A., Ábrányi‐Balogh, P., & Keserű, G. M. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112836 · Cited by 48
CETSA: A Target Engagement Assay with Potential to Transform Drug Discovery
Jensen, A. J., Molina, D. M., & Lundbäck, T. (2015) · Future Medicinal Chemistry · doi:10.4155/fmc.15.50 · Cited by 49
AI-Driven Polypharmacology in Small-Molecule Drug Discovery
Abdelsayed, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26146996 · Cited by 61
“For example, many approved kinase inhibitors in cancer therapy owe their clinical effectiveness to a broad target profile—they inhibit multiple kinases in oncogenic signaling cascades, thereby blocking cancer cell growth through parallel routes [11,12].”
Current Chemical Biology Tools for Studying Protein Phosphorylation and Dephosphorylation
Lu, C. H. S., Liu, K., Tan, L. P., & Yao, S. Q. (2011) · Chemistry - A European Journal · doi:10.1002/chem.201103206 · Cited by 48
An Open Library of Human Kinase Domain Constructs for Automated Bacterial Expression
Albanese, S. K., Parton, D. L., Işık, M., Rodríguez‐Laureano, L., Hanson, S. M., Behr, J. M., Gradia, S., Jeans, C., Levinson, N. M., Seeliger, M. A., et al. (2018) · Biochemistry · doi:10.1021/acs.biochem.7b01081 · Cited by 51
Recent Advances in Cancer Therapeutics
Chessum, N. E. A., Jones, K., Pasqua, E., & Tucker, M. (2015) · Progress in medicinal chemistry · doi:10.1016/bs.pmch.2014.11.002 · Cited by 49
Metadata
- Authors
- Knight, Z. A., Lin, H., & Shokat, K. M.
- Affiliations
- Rockefeller University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Knight, Zachary A.
- Shokat, Kevan M.
- Venue
- Nature reviews. Cancer
- Published
- 2010-02
- Volume
- 10
- Issue
- 2
- Pages
- 130-137
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC2880454
- OpenAlex
- W2022609682
- Cited by
- 674
- References
- 104
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 21 · 2023: 22 · 2022: 24 · 2021: 29 · 2020: 47 · 2019: 34 · 2018: 45 · 2017: 51 · 2016: 43 · 2015: 48 · 2014: 72 · 2013: 70 · 2012: 43
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5r01eb001987-15)
- National Institute of Diabetes and Digestive and Kidney Diseases (R00DK083531, K99DK083531)
- National Institute of Biomedical Imaging and Bioengineering (R01-EB001987)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- kinase inhibitors, polypharmacology, combination therapy, drug resistance, anticancer drug development
- MeSH terms
- Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Humans, Mutation, Neoplasms, Protein Kinases, Technology, Pharmaceutical, Drug Delivery Systems, Drug Resistance, Neoplasm, RNA, Small Interfering, Protein Kinase Inhibitors, Drug Discovery
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