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Inhibitors of farnesylation of Ras from a microbial natural products screening program
D Vilella1, M Sánchez, G Platas
1Centro de Investigación Básica, Natural Products Drug Discovery, Merck Sharp and Dohme de España, S.A. Josefa Valcárcel 38, 28027 Madrid, Spain.
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.
Insights
Natural products inhibit farnesyl protein transferase (FPTase), an enzyme crucial for Ras protein prenylation and tumor cell growth. This study reviews diverse FPTase inhibitors derived from microbial fermentations, offering unique mechanisms for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Natural Products Chemistry
Background:
- Mutant ras oncogenes are implicated in numerous human cancers, including pancreatic, colon, lung, thyroid, bladder, and leukemia.
- Ras protein prenylation, a post-translational modification involving a farnesyl group, is essential for membrane binding and plays a critical role in both normal and cancerous cell proliferation.
- Inhibitors of farnesyl protein transferase (FPTase), the enzyme responsible for Ras protein prenylation, have demonstrated efficacy in inhibiting tumor cell growth.
Purpose of the Study:
- To identify structurally diverse and unique inhibitors of FPTase.
- To explore natural products as a source for novel FPTase inhibitors.
- To review the mechanisms of action and origins of identified FPTase inhibitors.
Main Methods:
- Screening of natural products derived from microbial fermentations.
- Isolation and characterization of compounds from actinomycetes and fungi.
- Assay development for selective FPTase inhibition.
- Chemotaxonomic analysis of compound distribution among microorganisms.
Main Results:
- Identification of 10 distinct families of compounds that selectively inhibit FPTase.
- Discovery of compounds with various inhibitory mechanisms against FPTase.
- Isolation of these compounds from diverse microbial sources, including actinomycetes and fungi, from tropical and temperate regions.
- Characterization of the chemotaxonomic distribution of identified compounds across different microbial species.
Conclusions:
- Natural product screening is a viable strategy for discovering novel FPTase inhibitors.
- The identified compounds represent a diverse set of FPTase inhibitors with potential therapeutic applications in cancer.
- Microorganisms, particularly actinomycetes and fungi, are rich sources of structurally unique FPTase inhibitors.
- Chemotaxonomic analysis provides insights into the evolutionary and ecological distribution of these bioactive compounds.