Development of Grb2 SH2 Domain Signaling Antagonists: A Potential New Class of Antiproliferative Agents

Burke, Terrence R.

doi:10.1007/s10989-006-9014-7

Cited by 32 publications

(43 citation statements)

References 65 publications

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“…In contrast, the Grb2 SH2 domain binds high affinity ligands in β-turn conformations (Rahuel et al 1996; Ogura et al 1999). This unique binding mode suggests that highly specific inhibitors could be developed for this domain (Burke 2006). …”

Section: Introductionmentioning

confidence: 99%

Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor

et al. 2008

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The solution structure of the growth factor receptor-bound protein 2 (Grb2) SH2 domain complexed with a high-affinity inhibitor containing a non-phosphorus phosphate mimetic within a macrocyclic platform was determined by nuclear magnetic resonance (NMR) spectroscopy. Unambiguous assignments of the bound inhibitor and intermolecular NOEs between the Grb2 SH2 domain and the inhibitor was accomplished using perdeuterated Grb2 SH2 protein. The well-defined solution structure of the complex was obtained and compared to those by X-ray crystallography. Since the crystal structure of the Grb2 SH2 domain formed a domain-swapped dimer and several inhibitors were bound to a hinge region, there were appreciable differences between the solution and crystal structures. Based on the binding interactions between the inhibitor and the Grb2 SH2 domain in solution, we proposed a design of second-generation inhibitors that could be expected to have higher affinity.

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Section: Introductionmentioning

confidence: 99%

Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor

et al. 2008

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“…9 The current study has demonstrated that within a family of RCM-derived macrocycles typified by 2, considerable diversity in size, composition and ring junction stereochemistry is compatible with high affinity Grb2 SH2 domain binding. In contrast, the stereochemical requirements at the pTyr mimetic α-position appear to be more demanding.…”

Section: Discussionmentioning

confidence: 60%

Structural Examination of Ring-Closing Metathesis-Derived 15-Member Macrocycles as Grb2 SH2 Domain-Binding Tetrapeptide Mimetics

et al. 2007

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Ring-closing metathesis (RCM) was employed to join carboxy-terminal alkenyl glycine side chains together with vinyl-and allyl-functionality appended to the β-methylene of amino-terminal phosphotyrosyl (pTyr) mimetics. This required the synthesis of a variety of new pTyr mimetics, including a novel aza-containing analogue. Many of the resulting 15-member macrocyclic tetrapeptide mimetics exhibited low nanomolar Grb2 SH2 domain-binding affinities in spite of the fact that differing ring junction stereochemistries and geometries of the RCM-derived double bond were employed. The finding that significant latitude exists in the structural requirements for ring closure, may facilitate the development of therapeutically-relevant macrocyle-based Grb2 SH2 domain-binding antagonists. The synthetic approaches used in this study may also find application to peptide mimetics directed at other biological targets.

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“…Blocking the association of Grb2 and the growth factor with phosphopeptides or mimetics inhibits activation of RAS and the downstream MEK pathway. Readers are referred to excellent reviews on Grb2 as a cancer target [28] and on peptidomimetic inhibitor development [29]. …”

Section: Inhibitors Targeting Grb2mentioning

confidence: 99%

Targeting Sh2 Domains in Breast Cancer

et al. 2014

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Breast cancer is among the most commonly diagnosed cancer types in women worldwide and is the second leading cause of cancer-related disease in the USA. SH2 domains recruit signaling proteins to phosphotyrosine residues on aberrantly activated growth factor and cytokine receptors and contribute to cancer cell cycling, metastasis, angiogenesis and so on. Herein we review phosphopeptide mimetic and small-molecule approaches targeting the SH2 domains of Grb2, Grb7 and STAT3 that inhibit their targets and reduce proliferation in in vitro breast cancer models. Only STAT3 inhibitors have been evaluated in in vivo models and have led to tumor reduction. Taken together, these studies suggest that targeting SH2 domains is an important approach to the treatment of breast cancer.

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Development of Grb2 SH2 Domain Signaling Antagonists: A Potential New Class of Antiproliferative Agents

Cited by 32 publications

References 65 publications

Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor

Solution structure of the Grb2 SH2 domain complexed with a high-affinity inhibitor

Structural Examination of Ring-Closing Metathesis-Derived 15-Member Macrocycles as Grb2 SH2 Domain-Binding Tetrapeptide Mimetics

Targeting Sh2 Domains in Breast Cancer

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