Progress in the Development of Inhibitors of SH2 Domains

Cody, Wayne L.; Lin, Zhiwu; Panek, Robert L.; Rose, David W.; Rubin, John R.

doi:10.2174/1381612003401532

Cited by 55 publications

(33 citation statements)

References 151 publications

(222 reference statements)

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“…One possibility to overcome some of the limitations of forced protein expression is the use of small inhibitory molecules which only block the interaction(s) of a single protein domain. Inhibitory molecules for SH2 and SH3 domain binding pockets are currently being developed in the form of cell-penetrating peptides and small compounds (Cody et al, 2000;Kardinal et al, 2000Kardinal et al, , 2001. Their usefulness will critically depend on binding a nities but also on their ability to block with great selectivity only one or very few of the more than 300 SH2 and SH3 domains which exist in human cells.…”

Section: Do They Need To Meet?mentioning

confidence: 99%

Crk family adaptors–signalling complex formation and biological roles

2001

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Section: Do They Need To Meet?mentioning

confidence: 99%

Crk family adaptors–signalling complex formation and biological roles

2001

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“…Instead, most efforts are currently focussed on more traditional approaches to block the Grb2 SH2 domain ( [12,13,[15][16][17][286][287][288][289]; and references therein).…”

Section: Sosmentioning

confidence: 99%

“…When this balance becomes disturbed by bacterial or viral pathogens, toxins or genomic damage, a wide range of pathological consequences can manifest. Consequently, inhibitors for SH2 domains have been generated in several laboratories (reviewed in [12][13][14][15][16][17][18]). Much of this work has been carried out in pharmaceutical companies, so only a small amount of the gathered information is published.…”

mentioning

confidence: 99%

Potential Disease Targets for Drugs that Disrupt Protein - Protein Interactions of Grb2 and Crk Family Adaptors

Feller¹,

Lewitzky²

2006

CPD

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This review summarises some of the knowledge we have about Crk and Grb2 family adaptor protein signalling in health and disease and outlines the current status and the challenges still remaining in the development of efficient and selective inhibitors of their protein -protein interactions. It also highlights briefly some recent successes and problems of inhibitors for proteins that functionally interact with Crk and Grb2 family adaptors, as well as opportunities, which may arise from combination therapies. Grb2 and Crk family adaptors regulate signalling pathways linked to human diseases. They are mainly composed of Src homology 2 (SH2) and Src homology 3 (SH3) domains, which serve as docking sites for signalling proteins, including various receptors, cytoplasmic kinases and GTPase regulators. Considerable insight into the biological functions and mechanisms of action of small SH2/SH3 domain adaptors has been gained in the last years from experimental approaches as diverse as targeted gene disruption and structural studies at the atomic level. This has already indicated several strategies to utilise SH2 and SH3 domain interaction inhibitors in human disease therapy. Additional molecular targets for Crk and Grb2 domain interaction blockers are expected to surface as further protein-protein interactions are discovered. Examples include newly found DOCK family proteins (DOCK3, DOCK4, and DOCK5) which are known or suspected effectors of Crk proteins and the interaction of Grb2 with the cell cycle regulator p27Kip1.

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“…The compounds that induce protein interaction were called dimerizers [108][109][110]. Agents preventing this process are inhibitors of dimerization and antagonists of peptide/protein receptors [111][112][113][114][115][116][117].…”

Section: Protein-protein Interaction As Drug Target: Myth or Reality?mentioning

confidence: 99%

“…Numerous investigations were done in attempt to design the IDs for proteins possessing stable domains, which interact with receptors [114,[133][134][135][136][137][138]. Some proteins act as oligomer complexes, so IDs may prevent formation of the active dimer.…”

Section: Inhibitors Of Dimerizationmentioning

confidence: 99%

Protein‐protein interactions as a target for drugs in proteomics

et al. 2003

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Protein-protein interactions play a central role in numerous processes in the cell and are one of the main fields of functional proteomics. This review highlights the methods of bioinformatics and functional proteomics of protein-protein interaction investigation. The structures and properties of contact surfaces, forces involved in protein-protein interactions, kinetic and thermodynamic parameters of these reactions were considered. The properties of protein contact surfaces depend on their functions. The contact surfaces of permanent complexes resemble domain contacts or the protein core and it is reasonable to consider such complex formation as a continuation of protein folding. Characteristics of contact surfaces of temporary protein complexes share some similarities with active sites of enzymes. The contact surfaces of the temporary protein complexes have unique structure and properties and they are more conservative in comparison with active site of enzymes. So they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations were undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or, on the contrary, to induce protein dimerization.

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Progress in the Development of Inhibitors of SH2 Domains

Cited by 55 publications

References 151 publications

Crk family adaptors–signalling complex formation and biological roles

Crk family adaptors–signalling complex formation and biological roles

Potential Disease Targets for Drugs that Disrupt Protein - Protein Interactions of Grb2 and Crk Family Adaptors

Protein‐protein interactions as a target for drugs in proteomics

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