A large number of human cancers
are caused by the ras-oncogene-encoded p2l protein. This protein
contains single amino acid substitutions that cause it to become
oncogenic by inducing critical conformational changes in its three-dimensional
structure. It is the overall objective of the work proposed to employ
computer simulations of the three-dimensional structures oncogenic
ras-p2l to identify critical domains that dictate its permanently
activated state and to design peptides from these regions that will
selectively inhibit the action of oncogenic but not normal cellular
p2l. Based on the three-dimensional structures of these peptides,
using rational computer design, rigid analogues of these peptides
will be synthesized and tested for their abilities to cause reversion
of cancer cells to their normal phenotypes or to induce selective
destruction of the tumor cells with no toxicity to normal cells.
Several such agents have been designed and synthesized and are being
tested for this purpose. In addition, the selective anti-ras activities
of small molecules can be potentiated by ras-p2l peptides. New strategies
to introduce combination therapies with these agents are being designed.
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