title: Inhibitors of Ras-SOS Interactions.
abstract: Activating Ras mutations are found in about 30 % of human cancers. Ras activation is regulated by guanine nucleotide exchange factors, such as the son of sevenless (SOS), which form protein-protein interactions (PPIs) with Ras and catalyze the exchange of GDP by GTP. This is the rate-limiting step in Ras activation. However, Ras surfaces lack any evident suitable pockets where a molecule might bind tightly, rendering Ras proteins still 'undruggable' for over 30 years. Among the alternative approaches is the design of inhibitors that target the Ras-SOS PPI interface, a strategy that is gaining increasing recognition for treating Ras mutant cancers. Herein we focus on data that has accumulated over the past few years pertaining to the design of small-molecule modulators or peptide mimetics aimed at the interface of the Ras-SOS PPI. We emphasize, however, that even if such Ras-SOS therapeutics are potent, drug resistance may emerge. To counteract this development, we propose "pathway drug cocktails", that is, drug combinations aimed at parallel (or compensatory) pathways. A repertoire of classified cancer, cell/tissue, and pathway/protein combinations would be beneficial toward this goal.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China.
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Lu
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory, National Cancer Institute, Frederick, MD, 21702, USA.
authors.forename: Hyunbum
authors.initials: H
authors.lastname: Jang
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, 200025, China. jian.zhang@sjtu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory, National Cancer Institute, Frederick, MD, 21702, USA. NussinoR@helix.nih.gov.|Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Sackler Institute of Molecular Medicine, Tel Aviv University, Tel Aviv, 69978, Israel. NussinoR@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D020664:Son of Sevenless Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D010455:Peptides; D054852:Small Molecule Libraries; D020664:Son of Sevenless Proteins; D018631:ras Proteins
keywords: H-Ras; K-Ras; KRAS; oncogenic mutations; peptide mimetics; protein-protein interactions