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Journal ArticleDOI

Binding properties and biological characterization of new sugar-derived Ras ligands

Elena Sacco, +8 more
- 01 May 2011 - 
- Vol. 2, Iss: 5, pp 396-401
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TLDR
New, water-soluble Ras inhibitors composed by an aromatic pharmacofore moiety covalently linked to different sugars are presented, which bind to Switch 2 region of Ras, and inhibit GEF-catalyzed nucleotide exchange on Ras in vitro, and reduce Ras-dependent proliferation of murine fibroblasts.
Abstract: 
Since mutations of Ras genes have a great incidence in human tumours, Ras oncoproteins are a major clinical target for the development of anticancer agents. We have developed synthetic molecules able to inhibit Ras activation. Here we present new, water-soluble Ras inhibitors composed by an aromatic pharmacofore moiety covalently linked to different sugars. New glycosylated compounds bind to Switch 2 region of Ras, also involved in effector binding, inhibit GEF-catalyzed nucleotide exchange on Ras in vitro, and reduce Ras-dependent proliferation of murine fibroblasts. The influence of the sugar unit on Ras binding affinity and on the biological activity of Ras inhibitors has been investigated.

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Small-molecule modulation of Ras signaling

Jochen Spiegel, +4 more
- 01 Aug 2014 - 
TL;DR: Recently, new cavities on Ras for small-molecule ligands were identified, and selective direct targeting of mutated K-Ras(G12C) has become possible for the first time, and impairment of Ras spatial organization via targeting the prenyl-binding Ras chaperone PDEδ has opened a fresh perspective in anticancer research.
Journal ArticleDOI

Direct Attack on RAS: Intramolecular Communication and Mutation-Specific Effects

Kendra Marcus, +1 more
- 15 Apr 2015 - 
TL;DR: Structural networks of intramolecular communication between the RAS active site and membrane-interacting regions on the G-domain are disrupted in oncogenic mutants, which could have an effect on stabilization of conformational states of interest in attenuating signaling through RAS.
Journal ArticleDOI

Direct Modulation of Small GTPase Activity and Function

Philipp M. Cromm, +3 more
- 09 Nov 2015 - 
TL;DR: An overview of relevant aspects of the superfamily of small GTPases is given and recent progress and perspectives for the direct modulation of these challenging targets are summarized.
Journal ArticleDOI

Neoglycosylation and neoglycorandomization: enabling tools for the discovery of novel glycosylated bioactive probes and early stage leads

Randal D. Goff, +1 more
- 23 Jul 2014 - 
TL;DR: The fundamentals of neoglycosylation and the subsequent development of a 'neoglycorandomization' platform to afford differentially-glycosylated libraries of plant-based natural products, microbial-basednatural products, and small molecule-based drugs for drug discovery applications are discussed.
Journal ArticleDOI

Natural Compounds in Cancer Prevention: Effects of Coffee Extracts and Their Main Polyphenolic Component, 5-O-Caffeoylquinic Acid, on Oncogenic Ras Proteins.

Alessandro Palmioli, +8 more
- 19 Sep 2017 - 
TL;DR: By combining NMR spectroscopy, molecular docking, surface plasmon resonance and ex vivo assays of the Ras-dependent breast cancer cell line MDA-MB-231, the elucidation of the molecular basis of the activity of CGAs and natural extracts from green and roasted coffee beans as chemoprotective dietary supplements is contributed.
References
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Journal ArticleDOI

RAS oncogenes: the first 30 years

Marcos Malumbres, +1 more
- 01 Jun 2003 - 
TL;DR: The knowledge that has accumulated since their discovery 30 years ago has been remarkable, and should pave the way for not only solving the outstanding issues regarding RAS biology, but also for developing efficacious drugs that could have a significant impact on cancer treatment.
Journal ArticleDOI

GEFs and GAPs: Critical Elements in the Control of Small G Proteins

Johannes L. Bos, +2 more
- 01 Jun 2007 - 
TL;DR: GEFs and GAPs are multidomain proteins that are regulated by extracellular signals and localized cues that control cellular events in time and space and are potential therapeutic targets for developing drugs to treat various diseases, including cancer.
Journal ArticleDOI

Hyperactive Ras in developmental disorders and cancer.

Suzanne Schubbert, +2 more
- 01 Apr 2007 - 
TL;DR: The implications of germline mutations in the Ras–Raf–MEK–ERK pathway for understanding normal developmental processes and cancer pathogenesis are discussed.
Journal ArticleDOI

Essential role for oncogenic Ras in tumour maintenance

Lynda Chin, +14 more
- 29 Jul 1999 - 
TL;DR: The results provide genetic evidence that H-RasV12G is important in both the genesis and maintenance of solid tumours, and the failure of persistent endogenous and enforced VEGF expression to sustain tumour viability indicates that the tumour-maintaining actions of activated Ras extend beyond the regulation of V EGF expression in vivo.
Journal ArticleDOI

The structural basis of the activation of Ras by Sos

P.A. Boriack-Sjodin, +3 more
- 23 Jul 1998 - 
TL;DR: The crystal structure of human H-Ras complexed with the Ras guanine-nucleotide-exchange-factor region of the Son of sevenless (Sos) protein has been determined at 2.8 Å resolution and shows a structure that allows nucleotide release and rebinding.
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Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation.

Qi Sun, +8 more
- 18 Jun 2012 - 

GEFs and GAPs: Critical Elements in the Control of Small G Proteins

Johannes L. Bos, +2 more
- 01 Jun 2007 - 

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

Jonathan M. Ostrem, +4 more
- 28 Nov 2013 - 

Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity

Till Maurer, +19 more
- 03 Apr 2012 - 

A comprehensive survey of Ras mutations in cancer

Ian A. Prior, +2 more
- 15 May 2012 -