Title:Inhibiting the “Undruggable” RAS/Farnesyltransferase (FTase) Cancer
Target by Manumycin-related Natural Products
Volume: 29
Issue: 2
Author(s): Leandro Rocha Silva and Edeildo Ferreira da Silva-Júnior *
Affiliation:
- Institute of Chemistry and Biotechnology, Federal University of Alagoas, Lourival Melo Mota Avenue, 57072-970, Maceió,Brazil
Keywords:
Ras family, manumycin A, asukamycin, LL-C10037α, farnesyltransferase, geranylgeranyltransferase
Abstract: Cancer is an uncontrolled cell growth that can generate diverse types of cancer,
in which these will also present a different behavior in the face of pharmacological
treatment. These cancers’ types are found in one of the three categories, leukemias (also
named lymphomas), carcinomas, and sarcomas. In general, cancer's pathogenesis is associated
with three genetic mutations, where could emerge from oncogenes, tumor suppressor
genes, and/or genes responsible for regulating DNA replication. The term “undruggable”
is frequently related to the difficulty to design drugs to specific targets, such as
MYC, MYB, NF-κB, and RAS family of proteins. This last comprises more than 140 proteins,
and these are responsible for 30% of mutations in human cancers. Also, there are
three ras genes transcribed in human cells, called H-, K-, and N-ras oncogenes. Still, the
RAS proteins (farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase) enzymes)
perform essential steps in post-translational modification of eukaryotes cells,
such as (1) the farnesylation of the cysteine residue at the C-terminal tetrapeptide
CAAX; (2) proteolytic cleavage of the three C-terminal AAX oligopeptide; and (3) carboxymethylation
of the new C-terminal prenylated cysteine. Thus, the inhibition of this
undruggable RAS family of proteins has been considered a promising alternative to design
new anticancer agents since they are responsible for many types of human cancers.
Then, the manumycin A (obtained from the Streptomyces parvulus Tü64) and its analogs
(epoxyquinol core with or without their southern and eastern side chains; and dihydroxycyclohexenones
core) have been described as promising FTase inhibitors, which have demonstrated
their benefits against several types of cancer. In this review, a complete introduction
about cancer and its relation with RAS proteins is provided, as well as, the prenylation
mechanism of the cysteine residue is discussed in detail. Posteriorly, studies involving
manumycin-related compounds are described, showing some synthetic routes for obtaining
them and utilizing these natural products in monotherapies or combined therapies
with other anticancer drugs.
