c-Src Binds to the Cancer Drug Imatinib with an Inactive Abl/c-Kit Conformation and a Distributed Thermodynamic Penalty

Seeliger, Markus A.; Nagar, Bhushan; Frank, Filipp; Cao, Xuewen; Henderson, Max; Kuriyan, John

doi:10.1016/j.str.2007.01.015

Cited by 204 publications

(354 citation statements)

References 40 publications

(67 reference statements)

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“…For the uninhibited Hck*, a distinct conformation forms during the MD simulation and the backbone conformation formed by Asp404 is somewhat reminiscent of the "DFG-out" conformation, which is also characterized by a negative Asp404 φ angle of approximately -130 to -150 degree. For residues F405 and G406 the conformation of Hck*, however, is clearly distinct from the DFG-out conformation previously observed in inactive c-Src and Lck [42,43]. One might speculate that the Hck* backbone conformation either represents a novel stable topology or that the 30-ns structure 8 reflects a local energy minimum which is formed during a transition from the DFG-in to the DFG-out conformation.…”

Section: Comparison Of the Active Site Conformation To That Of Other mentioning

confidence: 77%

“…This structural feature also plays a critical role for the drug binding properties of tyrosine kinases [38][39][40][41][42][43].…”

Section: Effects Of the Sh3-sh2 Linker Sequence On The Activation Segmentioning

confidence: 99%

“…An interesting example comes from c-Src, which can adopt either a DFG-in or a DFG-out conformation. For wildtype c-Src, the DFG-out conformation is energetically quite unfavourable [44,43]. This is reflected in the low affinity of c-Src for the drug imatinib, which exclusively binds the DFGout conformation.…”

Section: Comparison Of the Active Site Conformation To That Of Other mentioning

confidence: 99%

“…This is reflected in the low affinity of c-Src for the drug imatinib, which exclusively binds the DFGout conformation. The structural origin for the low imatinib binding affinity of c-Src was also investigated by mutational studies [43]. The strongest increase in drug sensitivity was observed for three mutations (W260A, F405A, L407G), which destabilize the DFG-in conformation of c-Src.…”

Section: Comparison Of the Active Site Conformation To That Of Other mentioning

confidence: 99%

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Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase

Meiselbach

Sticht

2010

J Mol Model

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The coordination of activity in biological systems requires the existence of different signal transduction pathways that interact with one another and must be precisely regulated. The Src-family tyrosine kinases, which are found in many signaling pathways, differ in their physiological function despite their high overall structural similarity. In this context, the differences in the SH3-SH2 domain linkers might play a role for differential regulation, but the structural consequences of linker sequence are yet poorly understood. We have therefore performed comparative molecular dynamics simulations of wildtype Hck and of a mutant Hck, in which the SH3-SH2 domain linker is replaced by the sequence from the homologous kinase Lck. The simulations reveal that linker replacement does not only affect the orientation of the SH3 domain itself, but also leads to an alternative conformation of the activation segment in the Hck kinase domain. The sequence of the SH3-SH2 domain linker thus exerts a remote effect on the active site geometry and might therefore play a role in modulating the structure of the inactive kinase or for the fine-tuning of the activation process itself.

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Section: Comparison Of the Active Site Conformation To That Of Other mentioning

confidence: 77%

“…This structural feature also plays a critical role for the drug binding properties of tyrosine kinases [38][39][40][41][42][43].…”

Section: Effects Of the Sh3-sh2 Linker Sequence On The Activation Segmentioning

confidence: 99%

Section: Comparison Of the Active Site Conformation To That Of Other mentioning

confidence: 99%

Section: Comparison Of the Active Site Conformation To That Of Other mentioning

confidence: 99%

See 2 more Smart Citations

Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase

Meiselbach

Sticht

2010

J Mol Model

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“…For example, Imatinib hits c-SRC with an affinity that is at least 2000-fold lower than that for ABL2, although the binding sites of Abl2 and SRC are nearly identical even for the DFG-out state. 12 Kinase profiling data often contain many compounds from the same series. This makes it possible to discover chemical changes that lead to better selectivity.…”

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confidence: 99%

Targeted Kinase Selectivity from Kinase Profiling Data

Milletti

Hermann

2012

ACS Med. Chem. Lett.

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Kinase selectivity plays a major role in the design strategy of lead series and in the ultimate success of kinase drug discovery programs. Although profiling compounds against a large panel of protein kinases has become a standard part of modern drug discovery, data accumulated from these kinase panels may be underutilized for new kinase projects. We present a method that can be used to optimize the selectivity profile of a compound using historical kinase profiling data. This method proposes chemical transformations based on pairs of very similar compounds, which are both active against a desired target kinase and differ in activity against another kinase. We show that these transformations are transferable across scaffolds, thus making this tool valuable to exploit kinase profiling data for unrelated series of compounds.

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TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling

Marugán,

Sanz‐Gómez,

Ortigosa

et al. 2024

Molecular Oncology

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Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN‐positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN‐associated genes in an inducible manner. We find that the overexpression of targeting protein for Xklp2 (TPX2) enhances sensitivity to the proto‐oncogene c‐Src (SRC) inhibitor dasatinib due to activation of the Yes‐associated protein 1 (YAP) pathway. Furthermore, using breast cancer data from The Cancer Genome Atlas (TCGA) and a cohort of cancer‐derived patient samples, we find that both TPX2 overexpression and YAP activation are present in a significant percentage of cancer tumor samples and are associated with poor prognosis; therefore, they are putative biomarkers for selection for dasatinib therapy.

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c-Src Binds to the Cancer Drug Imatinib with an Inactive Abl/c-Kit Conformation and a Distributed Thermodynamic Penalty

Cited by 204 publications

References 40 publications

Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase

Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase

Targeted Kinase Selectivity from Kinase Profiling Data

TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling

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