Studying the Immunomodulatory Effects of Small Molecule Ras-Inhibitors in Animal Models of Rheumatoid Arthritis
Abstract
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. K/N-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 theRas/Raf/MEK/ERK1/2 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 H/N/K-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 K/N-Ras-dependent cancers.Thus, in collaboration with Concordia Pharmaceuticals Inc., FTS was developed into and oral drug, Salirasib (registered).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- AD1004135
Entities
People
- Yoel Kloog
Organizations
- Tel Aviv University