Discovery of Small Molecules that Bind to K‐Ras and Inhibit Sos‐Mediated Activation

Sun, Qi; Burke, Jason P.; Phan, Jason; Burns, Michael C.; Olejniczak, Edward T.; Waterson, Alex G.; Lee, Min Ho; Rossanese, Olivia W.; Fesik, Stephen W.

doi:10.1002/ange.201201358

Cited by 157 publications

(256 citation statements)

References 16 publications

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“…The binding site identified at the interface of HRas and SOS ('site B') corresponds to a site previously described in studies of uncomplexed Ras protein 5,6 ('site 2'). However, while Ras ligands 7 and 8, which were identified in these studies, inhibit SOS-mediated nucleotide exchange by preventing the binding of SOS to Ras, the fragments 5 and 6…”

Section: Fragment Binding Site B At the Hras:sos Interfacementioning

confidence: 81%

“…5,6 Comparison of published crystal structures with that of the HRas:SOS:5 complex shows that site B corresponds with the relatively shallow 'binding site 2' of the published fragments 7 and 8 on KRas (Fig. 3d).…”

Section: Fragment Binding Site B At the Hras:sos Interfacementioning

confidence: 96%

“…Indeed, in the previously described KRas fragment screen, inhibitors were reported to cross-react with both wild type K-and HRas. 5 We therefore sought to use the HRas:SOS binary complex to screen for potential ligands via X-ray crystallography, through a process of soaking 'cocktails' of small fragments into crystals of the complex. Such an approach has been reported in inhibitor design against the bacterial enzyme nucleoside 2-deoxyribosyltransferase.…”

Section: Introductionmentioning

confidence: 99%

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Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation

et al. 2015

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Constitutively active mutant KRas displays a reduced rate of GTP hydrolysis via both intrinsic and GTPaseactivating protein-catalysed mechanisms, resulting in the perpetual activation of Ras pathways. We describe a fragment screening campaign using X-ray crystallography that led to the discovery of three fragment binding sites on the Ras:SOS complex. The identification of tool compounds binding at each of these sites allowed exploration of two new approaches to Ras pathway inhibition by stabilising or covalently modifying the Ras:SOS complex to prevent the reloading of Ras with GTP. Initially, we identified ligands that bound reversibly to the Ras:SOS complex in two distinct sites, but these compounds were not sufficiently potent inhibitors to validate our stabilisation hypothesis. We conclude by demonstrating that covalent modification of Cys118 on Ras leads to a novel mechanism of inhibition of the SOS-mediated interaction between Ras and Raf, and is effective at inhibiting the exchange of labelled GDP in both mutant (G12C and G12V) and wild type Ras.

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Section: Fragment Binding Site B At the Hras:sos Interfacementioning

confidence: 81%

Section: Fragment Binding Site B At the Hras:sos Interfacementioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation

et al. 2015

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“…Although the potential therapeutic value and mechanism of action of these compounds are still under investigation, it is clear that they do not directly bind to Ras. Recent efforts by us (13) and others (14)(15)(16) toward direct inhibition of Ras have yielded promising initial results. For instance, using fragment screening, crystallography, and other methods, two groups reported ligands that directly bind Ras and inhibit GEF-dependent nucleotide exchange (15,16).…”

mentioning

confidence: 99%

“…Recent efforts by us (13) and others (14)(15)(16) toward direct inhibition of Ras have yielded promising initial results. For instance, using fragment screening, crystallography, and other methods, two groups reported ligands that directly bind Ras and inhibit GEF-dependent nucleotide exchange (15,16). However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active, GTP-loaded mutant Ras.…”

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confidence: 99%

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Hocker

Cho

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

134

133

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Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ∼15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several smallmolecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)-a bicyclic diterpenoid lactone isolated from Andrographis paniculata-and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras.cancer | molecular dynamics | allosteric site | drug design

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Overview of KRAS‐Driven Genetically Engineered Mouse Models of Non‐Small Cell Lung Cancer

Sheridan

Downward

2015

CP Pharmacology

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KRAS, the most frequently mutated oncogene in non-small cell lung cancer, has been utilized extensively to model human lung adenocarcinomas. The results from such studies have enhanced considerably an understanding of the relationship between KRAS and the development of lung cancer. Detailed in this overview are the features of various KRAS-driven genetically engineered mouse models (GEMMs) of non-small cell lung cancer, their utilization, and the potential of these models for the study of lung cancer biology.

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Discovery of Small Molecules that Bind to K‐Ras and Inhibit Sos‐Mediated Activation

Cited by 157 publications

References 16 publications

Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation

Small Molecule Binding Sites on the Ras:SOS Complex Can Be Exploited for Inhibition of Ras Activation

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

Overview of KRAS‐Driven Genetically Engineered Mouse Models of Non‐Small Cell Lung Cancer

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