In silico screening and biological evaluation of inhibitors of Src-SH3 domain interaction with a proline-rich ligand

Atatreh, Noor; Stojkoski, Cvetan; Smith, P.; Booker, Grant W.; Dive, Caroline; Frenkel, A. David; Freeman, Sally; Bryce, Richard A.

doi:10.1016/j.bmcl.2007.11.115

Cited by 21 publications

(8 citation statements)

References 27 publications

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“…Two Distinct Grb2SH3C-Gab2 Epitope Complexes Small molecule inhibitors that bind to SH3 domains or SH3 domain interacting motifs are currently not in advanced stages of development, but some early successes with both conven-tional and in silico screens have been reported (Atatreh et al, 2008;Betzi et al, 2007;Feller and Lewitzky, 2006;Feller et al, 2003). First in vivo studies of SH3 domain interaction blockers (C) Alignment of Gab protein sequences containing the Grb2 interaction motif a (PPPRPPKP).…”

Section: Structurementioning

confidence: 99%

Distinct Binding Modes of Two Epitopes in Gab2 that Interact with the SH3C Domain of Grb2

et al. 2009

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Grb2 and Gab2 form a complex implicated in normal cell signaling and cancer development. Binding of the Grb2SH3C domain to Gab2 is essential for the interaction, but molecular details remained undefined. Using peptide arrays and isothermal titration calorimetry, two Grb2SH3C binding sites in Gab2 (Gab2a and Gab2b) were confirmed and characterized. Gab2a bears similarity to a p27Kip1 epitope that also binds Grb2SH3C. Crystal structures of both Gab2 epitopes complexed with Grb2SH3C reveal that Gab2b contains a 3(10) helix that positions the arginine and lysine of the core-binding motif RxxK in parallel orientation. In contrast, the Gab2a RxxK motif is embedded in a PPII helix with Arg and Lys in staggered orientation. A similar interaction mode is also present in a new complex of Mona/GadsSH3C with an RxxxxK epitope from the putative phosphatase HD-PTP. In summary, our study reveals interaction types of SH3 domains, highlighting their great versatility.

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Section: Structurementioning

confidence: 99%

Distinct Binding Modes of Two Epitopes in Gab2 that Interact with the SH3C Domain of Grb2

et al. 2009

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“…Inhibition of C-Src could target proliferation, metastasis and angiogenesis in tumours, but the concomitant inhibition of N1-Src could be detrimental to promoting neuronal differentiation of brain cancers such as medulloblastoma and/or cause side effects in the developing pediatric brain. Peptidomimetic ligands of the C-Src SH3 have been developed that potently inhibit SH3 binding to proline rich motifs in vitro 38 , but these remain to be tested on the full length kinase or in cells. Finally, N1-Src-specific SH3 domain inhibitors based on PDN1 might be efficacious in other pathological processes in which inhibition of Src signalling in neurons has shown promise, such as ischemic excitotoxicity 39 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of N1-Src kinase by a specific SH3 peptide ligand reveals a role for N1-Src in neurite elongation by L1-CAM

Keenan

Wetherill

Ugbode

et al. 2017

Sci Rep

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In the mammalian brain the ubiquitous tyrosine kinase, C-Src, undergoes splicing to insert short sequences in the SH3 domain to yield N1- and N2-Src. We and others have previously shown that the N-Srcs have altered substrate specificity and kinase activity compared to C-Src. However, the exact functions of the N-Srcs are unknown and it is likely that N-Src signalling events have been misattributed to C-Src because they cannot be distinguished by conventional Src inhibitors that target the kinase domain. By screening a peptide phage display library, we discovered a novel ligand (PDN1) that targets the unique SH3 domain of N1-Src and inhibits N1-Src in cells. In cultured neurons, PDN1 fused to a fluorescent protein inhibited neurite outgrowth, an effect that was mimicked by shRNA targeting the N1-Src microexon. PDN1 also inhibited L1-CAM-dependent neurite elongation in cerebellar granule neurons, a pathway previously shown to be disrupted in Src−/− mice. PDN1 therefore represents a novel tool for distinguishing the functions of N1-Src and C-Src in neurons and is a starting point for the development of a small molecule inhibitor of N1-Src.

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“…Benzo[h]isoquinoline scaffold appears in compounds displaying a broad range of biological activity: D1 dopamine agonists [14][15][16], serotonin (5-HT2) receptor antagonists [17][18][19], histamine (H3) receptor antagonists [20,21], inhibitors of Chk1 kinase [22] and c-Src inhibitors [23].…”

Section: Introductionmentioning

confidence: 99%

Facile One-Pot Synthesis of Benzo[h]isoquinolines via Strong Acid Triggered [1,2]-Sigmatropic Rearrangement: A Theoretical and Experimental Studies

et al. 2019

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Benzo[h]isoquinoline scaffold is of interest as a rigid subunit that can be useful for constructing biologically active products. However, no good-yielded synthetic pathway to this ring system has been reported yet. Herein, a facile one-pot synthesis from N-aryl itaconimides and 1,3-diarylisobenzofuran via strong acid triggered skeletal rearrangement reaction is described. Theoretical study for this rearrangement is provided at M11/cc-pVDZ level of theory. Antitumor activity of obtained benzo[h]isoquinoline derivatives against human erythroleukemia K562 cell line was evaluated in vitro by MTS-assay.

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In silico screening and biological evaluation of inhibitors of Src-SH3 domain interaction with a proline-rich ligand

Cited by 21 publications

References 27 publications

Distinct Binding Modes of Two Epitopes in Gab2 that Interact with the SH3C Domain of Grb2

Distinct Binding Modes of Two Epitopes in Gab2 that Interact with the SH3C Domain of Grb2

Inhibition of N1-Src kinase by a specific SH3 peptide ligand reveals a role for N1-Src in neurite elongation by L1-CAM

Facile One-Pot Synthesis of Benzo[h]isoquinolines via Strong Acid Triggered [1,2]-Sigmatropic Rearrangement: A Theoretical and Experimental Studies

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