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EnglishRas 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.
(2021). The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells [journal article - articolo]. In FRONTIERS IN MOLECULAR BIOSCIENCES. Retrieved from http://hdl.handle.net/10446/177519
| Citazione: | (2021). The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells [journal article - articolo]. In FRONTIERS IN MOLECULAR BIOSCIENCES. Retrieved from http://hdl.handle.net/10446/177519 | |
| Titolo: | The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells | |
| Tipologia specifica: | articolo | |
| Tutti gli autori: | Tisi, Renata; Spinelli, Michela; Palmioli, Alessandro; Airoldi, Cristina; Cazzaniga, Paolo; Besoz...zi, Daniela; Nobile, Marco S; Mazzoleni, Elisa; Arnhold, Simone; De Gioia, Luca; Grandori, Rita; Peri, Francesco; Vanoni, Marco; Sacco, Elena | |
| Data di pubblicazione: | 2021 | |
| Abstract (eng): | 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. | |
| Rivista: | ||
| Nelle collezioni: | 1.1.01 Articoli/Saggi in rivista - Journal Articles/Essays |
File allegato/i alla scheda:
| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| fmolb-08-625979.pdf | publisher's version - versione editoriale |  | Open AccessVisualizza/Apri |
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