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Studying the Immunomodulatory Effects of Small Molecule Ras-Inhibitors in Animal Models of Rheumatoid Arthritis

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Technical Report,30 Sep 2014,29 Sep 2015

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Tel Aviv University TEL AVIV Israel

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Ras-GTPases are molecular switches that regulate key cellular processes, such as proliferation, differentiation, apoptosis, and motility. In T cells, Ras-family GTPases e.g. KN-Ras are crucialfor proper TCR-dependent activation following antigen recognition. Defective Ras GTPasessignaling has been associated with T cell anergy, and accordingly increased expression of activeRas was shown to reverse anergy and to restore IL-2 production. Importantly, T cells frompatients with Rheumatoid Arthritis RA display augmented activation of theRasRafMEKERK12 signaling pathway, and accordingly overexpression of active K-RAS innormal CD4 T cells has been shown to promote T cells reactivity to relevant autoantigen in RA.Thus, Ras GTPases appear to be a promising molecular target for inhibiting T cell activation inRA. Based on an innovative concept Kloog the partnering PI and colleagues discovered apotent non-toxic inhibitor of Ras, Farnesylthiosalicylic acid FTS. This small molecule does notbelong to the class of farnesyl transferase inhibitors FTIs that failed in clinical trials. Itinterferes with the interactions between Ras and distinct prenyl-binding chaperone proteins thatare vital for the proper plasma membrane PM localization and signaling dynamics of Ras-GTPases, and indeed FTS dislodges the classical HNK-Ras GTPases from the PM and inhibitstheir effective downstream signaling. In multiple preclinical animal studies it has been shownthat FTS effectively inhibited in vivo tumor growth of oncogenic KN-Ras-dependent cancers.Thus, in collaboration with Concordia Pharmaceuticals Inc., FTS was developed into and oral drug, Salirasib registered.

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