A small molecule–kinase interaction map for clinical kinase inhibitors

Fabian, Miles A.; Biggs, William H.; Treiber, Daniel K.; Atteridge, Corey E.; Azimioara, Mihai; Benedetti, Michael G.; Carter, Todd A.; Ciceri, Pietro; Edeen, Philip T.; Floyd, M. Brawner; Ford, J. Gair; Galvin, Margaret; Gerlach, Jay; Grotzfeld, Robert M.; Herrgård, Sanna; Insko, Darren E.; Insko, Michael A; Lai, Andiliy; Lélias, Jean-Michel; Mehta, Siddharth; Milanov, Zdravko V.; Velasco, Anne Marie; Wodicka, Lisa; Patel, Hitesh; Zarrinkar, Patrick P.; Lockhart, David J.

doi:10.1038/nbt1068

Cited by 1,751 publications

(1,728 citation statements)

References 37 publications

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“…The response to gefitinib and other EGFR inhibitors of patients expressing these mutants is therefore likely to reflect the dependence of their tumors on constitutive EGFR signaling per se, rather than any alteration in the response of mutated EGFR to the inhibitors. Consistent with this, recent studies of inhibitor binding (Fabian et al, 2005) have shown that none of the mutations analysed in our study alter gefitinib or erlotinib binding by more than threefold.…”

Section: Gefitinib-sensitizing Mutations Enhance Basal Egfr Autophospsupporting

confidence: 92%

EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer

2006

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Several somatic mutations within the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have been identified that predict clinical response of non-smallcell lung carcinoma (NSCLC) patients to gefitinib. To test the hypothesis that these mutations cause constitutive EGF receptor signaling, and to investigate its mechanistic basis, we expressed representative examples in a null background and analysed their biochemical properties. Each mutation caused significant EGF-independent tyrosine phosphorylation of EGFR, and allowed the receptor to promote Ba/F3 cell mitogenesis in the absence of EGF, arguing that these are oncogenic mutations. Active mutated receptors are present at the cell surface and are fully competent to bind EGF. Recent structural studies show that the inactive EGFR tyrosine kinase domain is autoinhibited by intramolecular interactions between its activation loop and aC helix. We find that mutations predicted to disrupt this autoinhibitory interaction (including several that have not been described in NSCLC) elevate EGF-independent tyrosine kinase activity, thus providing new insight into how somatic mutations activate EGFR and other ErbB family members.

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Section: Gefitinib-sensitizing Mutations Enhance Basal Egfr Autophospsupporting

confidence: 92%

EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer

2006

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“…There are two key features to clarify for each agent: first, the target responsible for cardiotoxicity and, second, the signalling pathway or pathways mediating the toxicity. None of the small-molecule inhibitors are truly selective, and some (for example, sunitinib) seem to be relatively non-selective 15 . Therefore, determining mechanisms of toxicity requires the identification of the specific target responsible.…”

Section: Grades Of Chfmentioning

confidence: 99%

“…In addition, making inhibitors less selective by design is also likely to result in the inhibition of several off-target kinases. Indeed, based on an approach that tested the binding affinity of several small-molecule inhibitors to 119 tyrosine and serine/threonine kinases, this clearly seems to be the case with sunitinib, which is expected to inhibit several off-target kinases at concentrations achieved in patients 15 (see below).…”

Section: R E V I E W Smentioning

confidence: 99%

“…Scanning the kinase interaction map identifies several candidates, including the ribosomal S6 kinase (RSK) family, which signals survival through inhibitory phosphorylation of the pro-apoptotic factor BAD, and AMP-activated protein kinase (AMPK), which has been reported to transduce pro-survival signals in the heart 46,70 . Indeed, the inhibitor-binding assay predicts that inhibition of RSKs and AMPK by sunitinib could be seen at clinically relevant concentrations 15 . FIGURE 3 illustrates hypothetical mechanisms by which sunitinib might lead to cardiotoxicity.…”

Section: R E V I E W Smentioning

confidence: 99%

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Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

2007

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“…Phosphorylation is arguably one of the best studied such modifications, and the ability to modulate phosphorylation status of key proteins is clinically desirable 43, 44, 45. Much progress has been made on understanding the role that protein kinases play in phosphorylating their targets and in understanding the specificity of compounds against the kinome 46, 47. In contrast, the progress on understanding the role the protein phosphatases play in dephosphorylating their targets has lagged behind.…”

Section: Discussionmentioning

confidence: 99%

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Lehmann

Bass

Barratt

et al. 2017

J cachexia sarcopenia muscle

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BackgroundSkeletal muscle is central to locomotion and metabolic homeostasis. The laboratory worm Caenorhabditis elegans has been developed into a genomic model for assessing the genes and signals that regulate muscle development and protein degradation. Past work has identified a receptor tyrosine kinase signalling network that combinatorially controls autophagy, nerve signal to muscle to oppose proteasome‐based degradation, and extracellular matrix‐based signals that control calpain and caspase activation. The last two discoveries were enabled by following up results from a functional genomic screen of known regulators of muscle. Recently, a screen of the kinome requirement for muscle homeostasis identified roughly 40% of kinases as required for C. elegans muscle health; 80 have identified human orthologues and 53 are known to be expressed in skeletal muscle. To complement this kinome screen, here, we screen most of the phosphatases in C. elegans . MethodsRNA interference was used to knockdown phosphatase‐encoding genes. Knockdown was first conducted during development with positive results also knocked down only in fully developed adult muscle. Protein homeostasis, mitochondrial structure, and sarcomere structure were assessed using transgenic reporter proteins. Genes identified as being required to prevent protein degradation were also knocked down in conditions that blocked proteasome or autophagic degradation. Genes identified as being required to prevent autophagic degradation were also assessed for autophagic vesicle accumulation using another transgenic reporter. Lastly, bioinformatics were used to look for overlap between kinases and phosphatases required for muscle homeostasis, and the prediction that one phosphatase was required to prevent mitogen‐activated protein kinase activation was assessed by western blot.ResultsA little over half of all phosphatases are each required to prevent abnormal development or maintenance of muscle. Eighty‐six of these phosphatases have known human orthologues, 57 of which are known to be expressed in human skeletal muscle. Of the phosphatases required to prevent abnormal muscle protein degradation, roughly half are required to prevent increased autophagy.ConclusionsA significant portion of both the kinome and phosphatome are required for establishing and maintaining C. elegans muscle health. Autophagy appears to be the most commonly triggered form of protein degradation in response to disruption of phosphorylation‐based signalling. The results from these screens provide measurable phenotypes for analysing the combined contribution of kinases and phosphatases in a multi‐cellular organism and suggest new potential regulators of human skeletal muscle for further analysis.

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A small molecule–kinase interaction map for clinical kinase inhibitors

Cited by 1,751 publications

References 37 publications

EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer

EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

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