Citation: Pincus, M.R.; Lin, B.; Patel, P.; Gabutan, E.; Zohar, N.; Bowne, W.B. Peptides That Block RAS-p21 Protein-Induced Cell Transformation. Biomedicines 2023, 11, 471. https:// doi.org/10.3390/biomedicines11020471 Academic Editor: William D. Lubell Received: 22 December 2022 Revised: 25 January 2023 Accepted: 1 February 2023 Published: 6 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). biomedicines Review Peptides That Block RAS-p21 Protein-Induced Cell Transformation Matthew R. Pincus 1, *, Bo Lin 1,2 , Purvi Patel 1 , Elmer Gabutan 1 , Nitzan Zohar 3 and Wilbur B. Bowne 3 1 Department of Pathology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA 2 AdventHealth, Department of Pathology, 301 Memorial Medical Pkwy, Daytona Beach, FL 32117, USA 3 Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, 1015 Walnut Street, Curtis Building, Suite 618, Philadelphia, PA 19107, USA * Correspondence: mrpincus2010@gmail.com or matthew.pincus@downstate.edu Abstract: 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. Keywords: RAS-p21 protein; oncogenic forms; peptides; small molecules; amino acid substitutions; mutant protein; cell transformation; blockade of oncogenic protein 1. Background Ras oncogenes that encode the RAS-p21 protein (Mr 21kDa, 189 amino acid residues) are known to be important causative factors in a large number of human cancers. Over 90 percent of pancreatic cancers, 40–50 percent of colon cancers, and about one-third of non-small-cell carcinomas of the lung express the ras oncogene [1]. This oncogene also occurs in a significant number of non-solid tissue tumors, such as acute myelogenous Biomedicines 2023, 11, 471. https://doi.org/10.3390/biomedicines11020471 https://www.mdpi.com/journal/biomedicines