期刊
CELLS
卷 5, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/cells5020026
关键词
cancer therapy; signal transduction; GTPase; Rho; Rho Lambda; Rac1; Cdc42; GEF
类别
资金
- Campus Alberta Innovation Program
- Medical Research Council
- Wellcome Trust
- BBSRC [BB/H019383/1, BB/I013865/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H019383/1, BBS/B/10714, BB/I013865/1] Funding Source: researchfish
Rho GTPases regulate cellular morphology and dynamics, and some are key drivers of cancer progression. This superfamily offers attractive potential targets for therapeutic intervention, with RhoA, Rac1 and Cdc42 being prime examples. The challenges in developing agents that act on these signaling enzymes include the lack of obvious druggable pockets and their membrane-bound activities. However, progress in targeting the similar Ras protein is illuminating new strategies for specifically inhibiting oncogenic GTPases. The structures of multiple signaling and regulatory states of Rho proteins have been determined, and the post-translational modifications including acylation and phosphorylation points have been mapped and their functional effects examined. The development of inhibitors to probe the significance of overexpression and mutational hyperactivation of these GTPases underscores their importance in cancer progression. The ability to integrate in silico, in vitro, and in vivo investigations of drug-like molecules indicates the growing tractability of GTPase systems for lead optimization. Although no Rho-targeted drug molecules have yet been clinically approved, this family is clearly showing increasing promise for the development of precision medicine and combination cancer therapies.
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