Last update 01 Nov 2024

GD2 x SRC

Last update 01 Nov 2024

Basic Info

Related Targets

GD2SRC

Drugs associated with GD2 x SRC

GD2-LP[Si306]

Target

GD2 x SRC

Mechanism

GD2 inhibitors [+1]

Active Org.

University of Siena [+1]

Originator Org.

University of Siena [+1]

Active Indication

Neuroblastoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GD2 x SRC

100 Translational Medicine associated with GD2 x SRC

0 Patents (Medical) associated with GD2 x SRC

Literatures (Medical) associated with GD2 x SRC

01 Feb 2010·Chemistry & Biology

Small-Molecule Ligands of GD2 Ganglioside, Designed from NMR Studies, Exhibit Induced-Fit Binding and Bioactivity

Article

Author: Kalle Gehring ; John W. Blankenship ; Enrico O. Purisima ; Karen Meerovitch ; William D. Lubell ; Shafinaz Chowdhury ; Karl Hansford ; Michael Gilbert ; Nai-Kong V. Cheung ; Martin Gagnon ; Tara Sprules ; Wenyong Tong ; H. Uri Saragovi

Ganglioside GD2 is a cell surface glycosphingolipid. Targeting of GD2, i.e., by anti-GD2 mAb 3F8, is used clinically for cancer diagnosis, prognosis, and therapy. Here, the conformations of free GD2, and of GD2 bound to mAb 3F8, were resolved by saturation transfer difference NMR and molecular modeling. Then, three small-molecule cyclic peptide ligands that bind to GD2 selectively were designed. Transferred nuclear Overhauser enhancement of the GD2-bound conformation of the peptide ligands showed an induced-fit binding mechanism. The mAb 3F8 and the peptidic GD2 ligands mediate similar biological functions in cell-based assays of calcium fluxes and src activation. Thus, small molecules can selectively and functionally interact with a sugar head group. This work furthers the concept of rationally designing ligands for carbohydrate targets, and may be expanded to other clinically relevant gangliosides.

PLOS ONEQ3 · CROSS-FIELD

Ligands Binding to Cell Surface Ganglioside GD2 Cause Src-Dependent Activation of N-Methyl-D-Aspartate Receptor Signaling and Changes in Cellular Morphology

Q3 · CROSS-FIELD

ArticleOA

Author: Saragovi, H Uri ; Gagnon, Martin ; Maira, Mario ; Tong, Wenyong

Ganglioside GD2 is a plasma membrane glycosphinogolipid. In healthy adults it is expressed at low levels, but it is over-expressed in many cancers. For cancer therapy, GD2 is targeted with anti-GD2 monoclonal antibodies (mAbs), and one adverse side effect is severe visceral pain. Pain is not neuropathic, cannot be blocked with morphine, and stops on discontinuation of mAb therapy. Here, we provide evidence that ligand binding to cell surface GD2 induces rapid and transient activation of Src-family kinases, followed by Src-dependent phosphorylation of NMDA-receptor NR2B subunits selectively, activation of Ca++ fluxes, production of cAMP, and changes in cellular morphology. These GD2-ligand activated signals differ in kinetics and in pharmacology from activation of the same signals in the same cells by BDNF, the growth factor agonist of the TrkB receptor, suggesting biological specificity. Hence, cell surface GD2 regulates pathways that can be associated with neoplasia and with morphine-intractable pain; and this can explain why expression of GD2 correlates with these two pathologies.

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