This is a review of approaches to the design of
peptides and small molecules that selectively block the oncogenic RAS-p21
protein in ras-induced
cancers. Single amino acid substitutions in this
protein, at critical positions such as at Gly 12 and Gln 61, cause the
protein to become oncogenic. These
mutant proteins cause over 90 percent of
pancreatic cancers, 40-50 percent of
colon cancers and about one third of non-small cell
cancers of the lung (NSCCL). RAS-p21 is a
G-protein that becomes activated when it exchanges
GDP for
GTP. Several promising approaches have been developed that target mutant (oncogenic) RAS-p21
proteins in these different
cancers. These approaches comprise: molecular simulations of mutant and wild-type
proteins to identify effector domains, for which
peptides can be made that selectively inhibit the oncogenic
protein that include PNC-1 (ras residues 115-126), PNC-2 (ras residues 96-110) and PNC7 (ras residues 35-47); the use of contiguous RAS-p21
peptide sequences that can block ras signaling;
cyclic peptides from large
peptide libraries and
small molecule libraries that can be identified in high throughput assays that can selectively stabilize inactive forms of RAS-p21; informatic approaches to discover
peptides and small molecules that dock to specific domains of RAS-p21 that can block mitogenic signal transduction by oncogenic RAS-p21; and the use of
cell-penetrating peptides (CPPs) that are attached to the variable domains of the anti-RAS-p21 inactivating
monoclonal antibody, Y13 259, that selectively enters oncogenic RAS-p21-containing
cancer cells, causing these cells to undergo apoptosis. Several new anti-oncogenic RAS-p21 agents, i.e., Amgen's
AMG510 and Mirati
Therapeutics'
MRTX849, polycyclic aromatic compounds, have recently been FDA-approved and are already being used clinically to treat RAS-p21-induced NSCCL and
colorectal carcinomas. These new drugs target the inactive form of RAS-p21 bound to
GDP with G12C substitution at the critical Gly 12 residue by binding to a groove bordered by specific domains in this
mutant protein into which these compounds insert, resulting in the stabilization of the inactive
GDP-bound form of RAS-p21. Other
peptides and small molecules have been discovered that block the G12D-RAS-p21 oncogenic
protein. These agents can treat specific
mutant protein-induced
cancers and are excellent examples of
personalized medicine. However, many oncogenic RAS-p21-induced
tumors are caused by other mutations at positions 12, 13 and 61, requiring other, more general anti-oncogenic agents that are being provided using alternate methods.