June 24, 2014
The present technology developed at the University of New Mexico is a pan inhibitor of small molecular weight GTPases with submicromolar activity against the Rab7GTPase measured using in vitro assays, as well as in cell-based assays.
Based on in vitro analyses, the compound behaves like a competitive inhibitor and docking studies show the compound can be accommodated in the nucleotide binding pocket of Rab7. In cell based assays, the compound may mimic the activated state of Rab7 and increases membrane bound Rab7. This can occur by compound binding promoting the transition of the Rab7 GTPase in to the GTP-bound conformation.
Ras and related small molecular weight GTPases function in the regulation of signaling and cell growth, and collectively serve to control cell proliferation, differentiation and apoptosis. The Ras-related GTPases are divided into four subfamilies with the Rab proteins regulation membrane transport, Rho proteins regulating cytoskeletal rearrangements and responses to signaling, Arf/Sar proteins regulating membrane and microtubule dynamics as well as protein transport, and Ran proteins controlling nucleocytoplasmic transport. There are currently no small molecules directed against Rab GTPases. Ras and Ras-related GTPase functions are tightly regulated, and dysregulation is casual in a wide variety of human diseases. Ras mutations resulting in impaired GTP hydrolysis and plasma membrane hyperactivation are linked to many human cancers. To date, inhibition of Ras and Ras-related proteins has relied largely on altering membrane recruitment with various drugs affecting prenylation. Generally, Ras proteins must be farnesylated for proper membrane localization, while Rab and Rho proteins are geranylated. Such strategies lack specificity and are problematic because each of these renylation machineries is required for the proper function of many Ras superfamily members. Rab7 is a regulator of transport from early to late endosomes and as such is critical for growth factor receptor down-regulation, for control of cell fate through autophagy pathways, nutrient uptake, immune cell regulation, to name a few.
The present technology developed at the University of New Mexico is a pan inhibitor of small molecular weight GTPases with submicromolar activity against the Rab7GTPase measured using in vitro assays, as well as in cell-based assays. Based on in vitro analyses, the compound behaves like a competitive inhibitor and docking studies show the compound can be accommodated in the nucleotide binding pocket of Rab7. In cell based assays, the compound may mimic the activated state of Rab7 and increases membrane bound Rab7. This can occur by compound binding promoting the transition of the Rab7 GTPase in to the GTP-bound conformation.
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docking studies show
nucleotide binding pocket
small molecules directed
impaired gtp hydrolysis
plasma membrane hyperactivation
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