Cited by 714Cancer Mechanisms and TherapyProtein Kinase Regulation and GTPase SignalingComputational Drug Discovery Methods

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Targeting the cancer kinome through polypharmacology

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Knight, Zachary A., Lin, Henry, Shokat, Kevan M.·2010·Nature reviews. Cancer

DOI 10.1038/nrc2787PMC PMC2880454

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Abstract

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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Background
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BackgroundInfluential
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“The GSK690693 results are consistent with the observation that pharmacological targeting of single kinases frequently results in limited efficacy (reviewed in [34]), although this does not imply that the in vivo therapeutic window will be increased by simultaneously targeting multiple signaling pathways.”
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“Therefore, the simultaneous inhibition of multiple activated TKs may be the best way to approach MTC [71–73].”
Background
Network-Based Strategies Can Help Mono- and Poly-pharmacology Drug Discovery: A Systems Biology View
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Background
Structural and Functional View of Polypharmacology
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“Such promiscuity can lead to detrimental off-target effects, but it can—and sometimes does—lead to favorable therapeutic outcome by targeting compensatory pathways (Knight et al., 2010).”
Background
Selective Targeting of AF9 YEATS Domain by Cyclopeptide Inhibitors with Preorganized Conformation
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“Notably, many of our experimental results are consistent with several anecdotal studies using kinase inhibitors against EGFR, MET and AKT2 (35-39).”
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“Highly selective inhibitors for these kinases have also been developed for cancer treatment as targeted therapies (Knight et al., 2010) .”
Background
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“Selective compounds are generated because they are thought to be less toxic and therefore better doseable to effective ranges [45].”
Background
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“In fact, the emergence of resistance to first-line TKIs has spawned the development of second- and third-generation therapies, combination therapies and concepts of polypharmacology [39].”
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“For example, this is by now well established for protein kinase inhibitors used in cancer therapy [4].”
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“The kinases were chosen for this study because of the strong family ties among kinases that manifest themselves through common structural features and predispose kinase inhibitors to polypharmacological action (Knight et al., 2010; Gani et al., 2015; Sidorov et al., 2015).”
Background
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“In contrast, the vast majority of clinically available therapeutics have multiple targets (Knight et al., 2010; Mestres et al., 2009).”
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“One such group of structurally similar small molecules found in this library is the sulfonylisoquinoline-containing molecules: H-89 (11), fasudil (12), and HA-1100 (13; also known as hydroxyfasudil).”
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“have pointed out, there is a need ‘for companies to collaborate to test new combinations of investigational drugs in oncology, where there is arguably the greatest need and opportunity’ [83].”
Background
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“Mutated oncoproteins, especially protein kinases, are the targets of most specific-target cancer drugs [16].”
Background
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Background
The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication
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“System-based approaches to drug discovery, such as network pharmacology, have exploited advances in chemical biology and network science to develop strategies for multitarget drugs and targeted drug combinations in the context of structural and biological networks [147 – 149].”
A Fluorescent Reporter of the Phosphorylation Status of the Substrate Protein STAT3
Lacey, V. K., Parrish, A., Han, S.-L., Shen, Z., Briggs, S., Ma, Y., & Wang, L. (2011) · Angewandte Chemie · doi:10.1002/anie.201102923 · Cited by 39
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The next steps in next-gen sequencing of cancer genomes
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“Whether a combination of highly selective agents or a single multitarget drug should be used upfront to simultaneously inhibit different pathways is unclear [17, 18].”
Background
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Background
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“The protein tyrosine kinases represent one example from this group that has seen rapid growth in the number of clinically approved inhibitory drugs, especially in oncology.(2) Remarkably, however, almost 70% of the kinase family members remain unexplored as drug targets.”
Background
KinaMetrix: a web resource to investigate kinase conformations and inhibitor space
Rahman, R., Ung, P. M. U., & Schlessinger, A. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky916 · Cited by 36
“(2) This table shows the probabilities of all conformational states for the uploaded structure.”
BackgroundInfluential
Phosphatidylinositol 3-Kinase Isoforms as Novel Drug Targets
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“, [332] and supported by Zunder et al.”
Method
Impact of phosphoproteomics in the translation of kinase‐targeted therapies
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“In occasions where tumors activate several pathways in parallel, or when pathway inhibition may result in the disruption of negative feedback loops, inhibiting more than one kinase-driven pathway may be needed to achieve complete responses [49].”
Background
Sunitinib-Containing Carborane Pharmacophore with the Ability to Inhibit Tyrosine Kinases Receptors FLT3, KIT and PDGFR-β, Exhibits Powerful In Vivo Anti-Glioblastoma Activity
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“This result is highly relevant as most tumors can circumvent the inhibition of a specific kinase either by de novo resistance, which refers to the failure of drugs to produce any detectable response after initial treatment, or by acquired resistance [33].”
Masitinib demonstrates anti‐proliferative and pro‐apoptotic activity in primary and metastatic feline injection‐site sarcoma cells*
Lawrence, J., Saba, C., Gogal, R. M., Lamberth, O., Vandenplas, M. L., Hurley, D. J., Dubreuil, P. C., Hermine, O., Dobbin, K. K., & Turek, M. (2011) · Veterinary and Comparative Oncology · doi:10.1111/j.1476-5829.2011.00291.x · Cited by 36
Human Disease and Drug Pharmacology, Complex as Real Life
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“However, soon thereafter it was found that imatinib is not at all as selective as initially thought as it could also interact with other protein targets such as the platelet-derived growth factor receptor (PDGF-R) and c-kit [80,81], among other kinases [82], its multikinase inhibitor profile directly accounting for it…”
Background
Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer
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“Recently, protein kinases has been reported to orchestrate the activation of signaling cascades in response to extracellular and intracellular stimuli to control cell growth, proliferation, survival and apoptosis [14, 15].”
Background
Identification of novel therapeutic targets in acute leukemias with NRAS mutations using a pharmacologic approach
Nonami, A., Sattler, M., Weisberg, E., Liu, Q., Zhang, J., Patricelli, M. P., Christie, A. L., Saur, A., Kohl, N. E., Kung, A. L., et al. (2015) · Blood · doi:10.1182/blood-2014-12-615906 · Cited by 34
“Previous studies have reported the complexity and exceptional difficulty of defining the mechanism of action of any multitargeted kinase inhibitor with certainty.(26,27) RAS mutations are known to activate a significant number of downstream effector pathways that have relative importance changes according to cellular…”
Background
Drug Repurposing for Epigenetic Targets Guided by Computational Methods
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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.
ORCID: Knight, Zachary A.
Shokat, Kevan M.
Venue: Nature reviews. Cancer
Publisher: Springer Science and Business Media LLC
Published: 2010-02
Volume: 10
Issue: 2
Pages: 130-137
ISSN: 1474-175X (ISSN-L)
1474-1768
DOI: 10.1038/nrc2787
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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Targeting the cancer kinome through polypharmacology

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