Inhibitors of farnesylation of Ras from a microbial natural products screening program

Abstract

Mutant ras oncogenes are associated with various human tumors such as pancreas, colon, lung, thyroid, bladder and several types of leukemia. Prenylation of Ras proteins plays a major role in cell proliferation of both normal and cancerous cells. Normal and oncogenic Ras proteins are posttranslationally modified by a farnesyl group that promotes membrane binding. Inhibitors of farnesyl protein transferase (FPTase), the enzyme that catalyzes the prenylation of Ras proteins, inhibit growth of tumor cells. In an effort to identify structurally diverse and unique inhibitors of FPTase, a program devoted to screening of natural products was initiated. This effort led to the identification of 10 different families of compounds, all of which selectively inhibit FPTase with a variety of mechanisms that are reviewed in this manuscript. These compounds originated from the fermentations of a number of microorganisms, either actinomycetes or fungi, isolated from different substrates collected in tropical and temperate areas. A chemotaxonomic discussion on the distribution of each compound among single or different types of microorganisms, either phylogenetically related or unrelated species, is included.

A method for the selection of production media for actinomycete strains based on their metabolite HPLC profiles

“…A common strategy, widely applied in industrial screening programs, consists in the application of several growth conditions (including variables such as production media, incubation time and other factors) to each strain studied [13]. Although there is strong anecdotal evidence that this approach improves the chances of finding the desired metabolite [1,14], there are practical limitations to the number of conditions used for each microorganism.…”

Nutritional requirements for the production of antimicrobial metabolites from Streptomyces

“…A common strategy, widely applied in industrial screening programs, consists of the application of several growth conditions (including variables such as production media, incubation time and other factors) to different strains which has been studied (Vilella et al, 2000). There is strong evidence that this approach improves the chances of finding the desired metabolites (Lauren and Yit-Heng, 2011;Arasu et al, 2013).…”

Search for Protein Farnesyltransferase Inhibitors of Microbial Origin: Our Strategy and Results as well as the Results Obtained by Other Groups

“…7 and reported respective PFTase inhibitory activities as well as the producing organisms are listed in Table 3. Some of the results, including ours, have been discussed in previously published reviews [45,46]. It should be noted that the values of PFTase inhibitory activities shown in Table 3 are not directly comparable for all cases, because they were obtained by several different methods using different enzyme sources and different acceptor peptides.…”