Inhibition of oncogenic Ras activation through small molecules is a promising approach to the pharmacologic treatment of human tumors. A common strategy to block Ras activation and signal transduction is based on molecules that interfere with the guanine exchange factors (GEF)-promoted nucleotide exchange. We developed several generations of small molecules active in inhibiting Ras activation at low micromolar concentrations. Some of these compounds are more active on cell lines expressing oncogenic Ras than on normal cells and are therefore good hit compounds for anticancer drug development. The molecules belonging to the last generation are soluble in water and allowed the identification of binding site on Ras by means of NMR experiments in deuterated water. The experimentally-determined Ras-binding site comprises residues belonging to the α-2 helix and the β-3 strand of the central β-sheet in the Switch 2 region. Synthetic molecules bind Ras in a region belonging to the more extended Ras/GEF-binding site, and a possible mechanism of Ras inhibition by these compounds can be the blockade of GEF-mediated nucleotide exchange. © 2013 Elsevier Inc.

Di Domizio, A., & Peri, F. (2013). Sugar-Based Inhibitors of Ras Activation: Biological Activity and Identification of Ras–Inhibitor Binding Interface. In The Enzymes, Inhibitors of the Ras Superfamily G-proteins, Part A (pp. 95-116). F. Tamanoi [10.1016/B978-0-12-416749-0.00005-1].

Sugar-Based Inhibitors of Ras Activation: Biological Activity and Identification of Ras–Inhibitor Binding Interface

Peri, F
2013

Abstract

Inhibition of oncogenic Ras activation through small molecules is a promising approach to the pharmacologic treatment of human tumors. A common strategy to block Ras activation and signal transduction is based on molecules that interfere with the guanine exchange factors (GEF)-promoted nucleotide exchange. We developed several generations of small molecules active in inhibiting Ras activation at low micromolar concentrations. Some of these compounds are more active on cell lines expressing oncogenic Ras than on normal cells and are therefore good hit compounds for anticancer drug development. The molecules belonging to the last generation are soluble in water and allowed the identification of binding site on Ras by means of NMR experiments in deuterated water. The experimentally-determined Ras-binding site comprises residues belonging to the α-2 helix and the β-3 strand of the central β-sheet in the Switch 2 region. Synthetic molecules bind Ras in a region belonging to the more extended Ras/GEF-binding site, and a possible mechanism of Ras inhibition by these compounds can be the blockade of GEF-mediated nucleotide exchange. © 2013 Elsevier Inc.
No
Scientifica
Capitolo o saggio
Ras, Medicinal chemistry, NMR, antitumoral compounds, sugars, carbohydrates
English
The Enzymes, Inhibitors of the Ras Superfamily G-proteins, Part A
978-0-12-416749-0
Di Domizio, A., & Peri, F. (2013). Sugar-Based Inhibitors of Ras Activation: Biological Activity and Identification of Ras–Inhibitor Binding Interface. In The Enzymes, Inhibitors of the Ras Superfamily G-proteins, Part A (pp. 95-116). F. Tamanoi [10.1016/B978-0-12-416749-0.00005-1].
Di Domizio, A; Peri, F
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/51963
Citazioni
  • Scopus 1
  • ???jsp.display-item.citation.isi??? 1
Social impact