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

Abstract

Mutant ras oncogenes are associated with various human tumors, being found in approximately 25% of all human cancers. Since its identification, the enzyme Ras protein farnesyltransferase (PFTase), which catalyzes the initial step of Ras-processing, has been viewed as a most promising target for cancer therapy. Consequently, a number of synthetic and natural small molecules have been searched and developed according to this concept during the 1990s. Among these, microbial metabolites have provided diverse structural classes of compounds which exhibit PFTase inhibitory activity. This article reviews our work on PFTase inhibitors originating from microbial metabolites, and the results of similar works carried out by several other research groups.

Exploring the Diversity and Antibacterial Potentiality of Cultivable Actinobacteria from the Soil of the Saxaul Forest in Southern Gobi Desert in Mongolia

“…Strain MGa5-5 produced granaticin A and dihydrogranaticin A as the major active metabolites with some minor components of dihydrolated and deacetylated derivatives, but granaticin B or dihydrogranaticin B was undetected therein. Extensive biological activities have been reported for granaticins, including antibacterial, antiprotozoal and cytotoxic activities [ 41 , 42 , 43 , 44 ], and they were reported as multi-targeted enzyme inhibitors on both prokaryotes and higher organisms, such as Leucyl-tRNA synthetase [ 99 , 100 ], farnesyltransferase (FTase) [ 101 ], inosine 5′-monophosphate dehydrogenase (IMPDH) [ 102 ] and cell division cycle kinase (Cdc7) [ 103 ]. In recent years, some derivatives of granaticin have been used in pharmaceuticals as an excipient for treating proliferative disease or to treat diseases such as Hartnup syndrome [ 104 ].…”

Chemistry and Biology of Acyloin Natural Products

“…Aspirin was used as a positive control, giving an IC 50 value of 289.5 ± 15.7 M. At the 50 M level, inhibition levels between 52.9 ± 5.5% to 96.0 ± 0.1% were observed for all xenocyloins, with xenocyloins G (26) and H (27) being the most active compounds. Xenocyloin H (27) was the most active compound, and an IC 50 value of 27.5 ± 3.5 M was obtained, whilst xenocyloin G (26) was slightly less active, exhibiting an IC 50 of 31.7 ± 4.4 M, both compounds were significantly more active than the aspirin control.…”

Exploration of Aspergillus fumigatus Ras pathways for novel antifungal drug targets

“…Protein trafficking and subsequent membrane association of many proteins is typically mediated by hydrophobic transmembrane domains. However, Ras proteins lack such domains, and therefore the protein undergoes several PTMs at the CAAX box and the palmitoylated cysteine motif which convert the HVR to a hydrophobic, membrane-associated domain (Figure 1A) (Takai et al, 2001; Hancock, 2003; Larsen et al, 2006; Iwasaki and Ōmura, 2007). …”