Ras oncoproteins play a crucial role in the onset, maintenance, and progression of the most common and deadly human cancers. Despite extensive research efforts, only a few mutant-specific Ras inhibitors have been reported. We show that cmp4-previously identified as a water-soluble Ras inhibitor- targets multiple steps in the activation and downstream signaling of different Ras mutants and isoforms. Binding of this pan-Ras inhibitor to an extended Switch II pocket on HRas and KRas proteins induces a conformational change that down-regulates intrinsic and GEF-mediated nucleotide dissociation and exchange and effector binding. A mathematical model of the Ras activation cycle predicts that the inhibitor severely reduces the proliferation of different Ras-driven cancer cells, effectively cooperating with Cetuximab to reduce proliferation even of Cetuximab-resistant cancer cell lines. Experimental data confirm the model prediction, indicating that the pan-Ras inhibitor is an appropriate candidate for medicinal chemistry efforts tailored at improving its currently unsatisfactory affinity.

Tisi, R., Spinelli, M., Palmioli, A., Airoldi, C., Cazzaniga, P., Besozzi, D., et al. (2021). The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells. FRONTIERS IN MOLECULAR BIOSCIENCES, 8(17 February 2021) [10.3389/fmolb.2021.625979].

The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells

Tisi, Renata
Co-primo
;
Spinelli, Michela
Co-primo
;
Palmioli, Alessandro;Airoldi, Cristina;Besozzi, Daniela;Nobile, Marco S;Mazzoleni, Elisa;De Gioia, Luca;Grandori, Rita;Peri, Francesco;Vanoni, Marco
Penultimo
;
Sacco, Elena
Ultimo
2021

Abstract

Ras oncoproteins play a crucial role in the onset, maintenance, and progression of the most common and deadly human cancers. Despite extensive research efforts, only a few mutant-specific Ras inhibitors have been reported. We show that cmp4-previously identified as a water-soluble Ras inhibitor- targets multiple steps in the activation and downstream signaling of different Ras mutants and isoforms. Binding of this pan-Ras inhibitor to an extended Switch II pocket on HRas and KRas proteins induces a conformational change that down-regulates intrinsic and GEF-mediated nucleotide dissociation and exchange and effector binding. A mathematical model of the Ras activation cycle predicts that the inhibitor severely reduces the proliferation of different Ras-driven cancer cells, effectively cooperating with Cetuximab to reduce proliferation even of Cetuximab-resistant cancer cell lines. Experimental data confirm the model prediction, indicating that the pan-Ras inhibitor is an appropriate candidate for medicinal chemistry efforts tailored at improving its currently unsatisfactory affinity.
Articolo in rivista - Articolo scientifico
Raf1 binding; RasG12V; RasG13D; anti-cancer agent; cetuximab; exchange factor; intrinsic nucleotide dissociation and exchange; mathematical modeling & simulation
English
2021
8
17 February 2021
625979
open
Tisi, R., Spinelli, M., Palmioli, A., Airoldi, C., Cazzaniga, P., Besozzi, D., et al. (2021). The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells. FRONTIERS IN MOLECULAR BIOSCIENCES, 8(17 February 2021) [10.3389/fmolb.2021.625979].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/306924
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