2021
DOI: 10.1016/j.apsb.2021.02.014
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Abstract: RAS, a member of the small GTPase family, functions as a binary switch by shifting between inactive GDP-loaded and active GTP-loaded state. RAS gain-of-function mutations are one of the leading causes in human oncogenesis, accounting for ∼19% of the global cancer burden. As a well-recognized target in malignancy, RAS has been intensively studied in the past decades. Despite the sustained efforts, many failures occurred in the earlier exploration and resulted in an ‘undruggable’ feature of RAS proteins. Phospho… Show more

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Cited by 20 publications
(11 citation statements)
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“…In the past two decades, with an in-depth understanding of allostery and the expeditious development of structural biology and computational biology tools, a series of emerging experimental and computational approaches for the development of allosteric drugs have commenced. The flurry of research into allosteric regulation has shown great potential for allosteric drug therapeutic development, such as oncoprotein Ras, G protein-coupled receptors, and protein kinases. A number of site-oriented experimental approaches have been applied to detect allosteric sites, such as alanine-scanning mutagenesis, high-throughput screening, disulfide trapping, patch-clamp fluorometry, fragment-based screening, H/D exchange mass spectrometry, and photoaffinity labeling . Nevertheless, these experimental approaches are costly, time-consuming, arduous to cope with the challenges of the rapidly increasing number of allosteric drug targets, and incapable of identifying cryptic allosteric sites of proteins.…”
Section: Introductionmentioning
confidence: 99%
“…In the past two decades, with an in-depth understanding of allostery and the expeditious development of structural biology and computational biology tools, a series of emerging experimental and computational approaches for the development of allosteric drugs have commenced. The flurry of research into allosteric regulation has shown great potential for allosteric drug therapeutic development, such as oncoprotein Ras, G protein-coupled receptors, and protein kinases. A number of site-oriented experimental approaches have been applied to detect allosteric sites, such as alanine-scanning mutagenesis, high-throughput screening, disulfide trapping, patch-clamp fluorometry, fragment-based screening, H/D exchange mass spectrometry, and photoaffinity labeling . Nevertheless, these experimental approaches are costly, time-consuming, arduous to cope with the challenges of the rapidly increasing number of allosteric drug targets, and incapable of identifying cryptic allosteric sites of proteins.…”
Section: Introductionmentioning
confidence: 99%
“…Ras is a member of the small GTPase family and is the switch controlling GDP and GTP conversion. Functional mutations in Ras are one of the main causes of tumorigenesis [ 64 ]. The human Ras family includes four homologous Ras proteins: H-Ras, N-Ras, and two K-Ras splice variants (K-Ras4A and K-Ras4B), and are encoded by three RAS genes, HRAS, NRAS, and KRAS.…”
Section: The Signaling Pathways In Tumor Drug Resistancementioning
confidence: 99%
“…The human Ras family includes four homologous Ras proteins: H-Ras, N-Ras, and two K-Ras splice variants (K-Ras4A and K-Ras4B), and are encoded by three RAS genes, HRAS, NRAS, and KRAS. Across all tumors caused by Ras mutations, K-Ras, N-Ras, and H-Ras mutations account for 85%, 12%, and 3%, respectively [ 64 ]. Studies have shown that oncogenic K-Ras mutations are closely associated with tumor resistance to platinum drugs [ 65 ].…”
Section: The Signaling Pathways In Tumor Drug Resistancementioning
confidence: 99%
“…Three main strategies have been proposed to treat RAS-related cancers: (I) targeting the signaling pathway upstream of RAS, such as vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), or the phosphorylation of upstream regulatory kinases [ 32 ]; (II) targeting RAS downstream signaling, such as RAF [ 33 ], MEK [ 34 ], ERK [ 35 ], PI3K [ 36 ], AKT [ 37 ], or mTOR [ 38 ]; (III) directly targeting RAS itself. However, in the absence of a deep pocket for binding small compounds with high affinity, RAS has long been considered undruggable [ 39 , 40 ].…”
Section: Biochemical Features Of Rasmentioning
confidence: 99%