Sulindac‐Derived Ras Pathway Inhibitors Target the Ras–Raf Interaction and Downstream Effectors in the Ras Pathway

Waldmann, Herbert; Karaguni, Ioanna‐Maria; Carpintero, Mercedes; Gourzoulidou, Eleni; Herrmann, Christian; Brockmann, Christoph; Oschkinat, Hartmut; Müller, Oliver

doi:10.1002/anie.200353089

Cited by 79 publications

(28 citation statements)

References 7 publications

(7 reference statements)

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“…In the following paper, [16] we demonstrate that the majority of the compounds shown in Table 1 interfere with the Ras-Raf interaction. Such a screen may additionally yield compounds that target the pathway employed for counterscreening, [17] which renders the entire library synthesis, as well as the biological and biochemical investigations, very efficient.…”

Section: Methodsmentioning

confidence: 97%

Identification of Potent Ras Signaling Inhibitors by Pathway‐Selective Phenotype‐Based Screening

et al. 2004

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Section: Methodsmentioning

confidence: 97%

Identification of Potent Ras Signaling Inhibitors by Pathway‐Selective Phenotype‐Based Screening

et al. 2004

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“…7, 8 Also, Ras proteins do not have accessible pockets on their surface. Despite these difficulties, a few recent studies report allosteric 9-12 and covalent inhibitors 13, 14 of mutant K-Ras. Additional approaches include inhibition of downstream effectors (e.g., kinases) and proteins essential for transformative growth in the presence of oncogenic Ras.…”

Section: Introductionmentioning

confidence: 99%

8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells

Mohammed

Hampton

Ashall

et al. 2016

Bioorganic & Medicinal Chemistry

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Ras converting enzyme 1 (Rce1) is an endoprotease that catalyzes processing of the C-terminus of Ras protein by removing -aaX from the CaaX motif. The activity of Rce1 is crucial for proper localization of Ras to the plasma membrane where it functions. Ras is responsible for transmitting signals related to cell proliferation, cell cycle progression, and apoptosis. The disregulation of these pathways due to constitutively active oncogenic Ras can ultimately lead to cancer. Ras, its effectors and regulators, and the enzymes that are involved in its maturation process are all targets for anticancer therapeutics. Key enzymes required for Ras maturation and localization are the farnesyltransferase (FTase), Rce1, and isoprenylcysteine carboxyl methyltransferase (ICMT). Among these proteins, the physiological role of Rce1 in regulating Ras and other CaaX proteins has not been as fully explored. Small-molecule inhibitors of Rce1 could be useful as chemical biology tools to understand further the downstream impact of Rce1 on Ras function and serve as potential leads for cancer therapeutics. Structure-activity relationship (SAR) analysis of a previously reported Rce1 inhibitor, NSC1011, has been performed to generate a new library of Rce1 inhibitors. The new inhibitors caused a reduction in Rce1 in vitro activity, exhibited low cell toxicity, and induced mislocalization of EGFP-Ras from the plasma membrane in human colon carcinoma cells giving rise to a phenotype similar to that observed with siRNA knockdowns of Rce1 expression. Several of the new inhibitors were more effective at mislocalizing K-Ras compared to a potent farnesyltransferase inhibitor (FTI), which is significant because of the preponderance of K-Ras mutations in cancer.

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“…Combining the information obtained from fragments that bind at different regions of the binding pocket, these fragments can be chemically linked to yield new molecules with increased binding affinity. 1 H-15 N-HSQC spectra have also been used to determine that sulindac-derived inhibitors of the Ras-Raf interaction [221] bind directly to Ras. This is a relevant result not only with respect to the particular studied system, but it also shows the technique to be suitable for facilitating the task of finding binding sites at the target (see Section 4).…”

Section: Guided Docking Using Chemical Shifts Perturbations (Csp)mentioning

confidence: 99%

Targeting Protein-Protein Interactions with Small Molecules: Challenges and Perspectives for omputational Binding Epitope Detection and Ligand Finding

González-Ruiz

Gohlke²

2006

CMC

167

114

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A promising way to interfere with biological processes is through the control of protein-protein interactions by means of small molecules that modulate the formation of protein-protein complexes. Although the feasibility of this approach has been demonstrated in principle by recent results, many of the small-molecule modulators known to date have not been found by rational design approaches. In large part this is due to the challenges that one faces in dealing with protein binding epitopes compared to, e.g., enzyme binding pockets. Recent advances in the understanding of the energetics and dynamics of protein binding interfaces and methodological developments in the field of structure-based drug design methods may open up a way to apply rational design approaches also for finding protein-protein interaction modulators. These advances and developments include (I) computational approaches to dissect binding interfaces in terms of energetic contributions of single residues (to identify "hot spot" residues), (II) prediction of potential binding sites from unbound protein structures, (III) recognition of allosteric binding sites as alternatives to directly targeting interfaces, (IV) docking approaches that consider protein flexibility and improved descriptions of the solvent influence on electrostatic interactions, and (V) data-driven docking approaches. Here, we will summarize these developments with a particular emphasis on their applicability to screen for or design small-molecule modulators of protein-protein interactions.

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Sulindac‐Derived Ras Pathway Inhibitors Target the Ras–Raf Interaction and Downstream Effectors in the Ras Pathway

Abstract: In the preceding article [1] we introduced a method to synthesize a library of compounds structurally based on the nonsteroidal antiinflammatory drug (NSAID) sulindac (1,[*] Dr.

Cited by 79 publications

References 7 publications

Identification of Potent Ras Signaling Inhibitors by Pathway‐Selective Phenotype‐Based Screening

Identification of Potent Ras Signaling Inhibitors by Pathway‐Selective Phenotype‐Based Screening

8-Hydroxyquinoline-based inhibitors of the Rce1 protease disrupt Ras membrane localization in human cells

Targeting Protein-Protein Interactions with Small Molecules: Challenges and Perspectives for omputational Binding Epitope Detection and Ligand Finding

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