The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index; 14 of the 23 sources its claims cite were checked for support.
Discovery and characterization of small molecules that target the GTPase Ral
Open accessAbstract
The Ras-like GTPases RalA and RalB are important drivers of tumour growth and metastasis. Chemicals that block Ral function would be valuable as research tools and for cancer therapeutics. Here we used protein structure analysis and virtual screening to identify drug-like molecules that bind to a site on the GDP-bound form of Ral. The compounds RBC6, RBC8 and RBC10 inhibited the binding of Ral to its effector RALBP1, as well as inhibiting Ral-mediated cell spreading of murine embryonic fibroblasts and anchorage-independent growth of human cancer cell lines. The binding of the RBC8 derivative BQU57 to RalB was confirmed by isothermal titration calorimetry, surface plasmon resonance and 1H–15N transverse relaxation-optimized spectroscopy (TROSY) NMR spectroscopy. RBC8 and BQU57 show selectivity for Ral relative to the GTPases Ras and RhoA and inhibit tumour xenograft growth to a similar extent to the depletion of Ral using RNA interference. Our results show the utility of structure-based discovery for the development of therapeutics for Ral-dependent cancers.
Overview
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Written from the paper’s full text.
TL;DR
Structure-based virtual screening identified small molecules that bind the GDP-bound form of Ral GTPases and inhibit Ral signaling, cell growth, and xenograft tumor growth. RBC8 and its derivative BQU57 act selectively through RalA/RalB and show efficacy in Ral-dependent lung cancer models.
Key findings
- Docking 500,000 ChemDiv compounds to an allosteric site on RalA-GDP yielded 88 candidates; RBC6, RBC8, and RBC10 inhibited RalA activation in cells, Ral-dependent MEF spreading, and anchorage-independent growth, while RBC5, RBC7, and RBC42 were inactive controls.
- BQU57 bound RalB-GDP with KD = 7.7 ± 0.6 μM by ITC and KD = 4.7 ± 1.5 μM by SPR; RBC8 and BQU57 showed selectivity for Ral over Ras and RhoA and did not bind RalB-GNP.
- In soft agar, RBC8 IC50 was 3.5 μM in H2122 and 3.4 μM in H358; BQU57 IC50 was 2.0 μM in H2122 and 1.3 μM in H358. Ral-dependent lines H2122 and H358 were sensitive, whereas H460 and Calu6 were not.
- In H2122 xenografts, RBC8 at 50 mg/kg/d for 21 days inhibited tumor growth similarly to dual RalA/RalB knockdown; BQU57 showed dose-dependent inhibition at 10, 20, and 50 mg/kg/d, and both compounds inhibited RalA/RalB but not Ras or RhoA activity in tumors.
Methods
- Structure-based virtual screening: compared RalA-GDP, RalA-GNP-exo84, and RalA-GNP-sec5 structures to identify an allosteric site; docked 500,000 ChemDiv compounds into RalA-GDP and selected 88 for testing.
- Cell-based assays: RalA activity ELISA in J82 cells expressing FLAG-RalA; MEF spreading in wild-type versus Cav1−/− cells; soft agar colony formation in H2122, H358, H460, and Calu6 cells, including siRNA knockdown and constitutively active RalAG23V/RalBG23V rescue.
- Biophysical and in vivo methods: 15N-HSQC NMR, ITC, and SPR for binding; LC-MS/MS for cellular uptake and pharmacokinetics; nude mouse xenografts with H2122 or H358 cells; RalBP1, Ras, and RhoA pull-down assays for activity.
Limitations
- The paper states that additional medicinal chemistry optimization is required and describes the compounds as a first generation of tools.
- The paper states that no RalB-GDP crystal structure is available, so a homology model was used and docking could not be performed on RalB-GDP; RalB-GDP binding was instead assessed by NMR.
- The paper notes that mouse randomization was done but no blinding was performed; stable overexpression of FLAG-RalAG23V or FLAG-RalBG23V in H2122 cells was unsuccessful, so those rescue experiments used transient transfection.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
14 of 23 cited sources checked · 6 supported · 1 flagged · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“genetically engineered mouse models revealed substantial redundancy for Ral proteins in tumorigenesis12.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Supportedcites [12] Peschard, P. et al. Genetic deletion of RALA and RALB small GTPases reveals redundant functions in development and tumorigenesis. Curr. Biol. 22, 2063–2068 (2012) source
In Results and Discussion (page not provided), the authors report that deleting either Rala or Ralb did not impair tumor formation in their mouse models. In the Kras-driven lung cancer model, they found that RAL function was essential but either RALA or RALB was sufficient, directly supporting redundancy in tumorigenesis. (LLM, conf=0.94)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Active Ral activates cellular processes through effectors including Ral Binding Protein 1 (RalBP1, RLIP76 or RIP17), Sec5/Exo85, filamin, and phospholipase D18–10.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Not checked — no full text of the sourcecites [7] Awasthi, S., Sharma, R., Singhal, S. S., Zimniak, P. & Awasthi, Y. C. RLIP76, a novel transporter catalyzing ATP-dependent efflux of xenobiotics. Drug Metab. Dispos. 30, 1300–1310 (2002) source
- Not checked — no full text of the sourcecites [8] Oxford, G. et al. RalA and RalB: antagonistic relatives in cancer cell migration. Cancer Res. 65, 7111–7120 (2005) source
- Partly supportedcites [9] Lim, K. H. et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 7, 533–545 (2005) sourceExperimental — accuracy not yet measured
The passages on RalA effector binding identify RalBP1, filamin, PLD1, and the exocyst subunits Sec5 and Exo84. The claim says “Sec5/Exo85,” but our copy names Exo84, not Exo85. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesEvery source the paper cites for this claim was checked and supports it.
In the paper
“Its proximity to the previously described C3bot binding site17 supports the notion that small molecule occupancy at this site could inhibit function.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Supportedcites [17] Pautsch, A., Vogelsgesang, M., Trankle, J., Herrmann, C. & Aktories, K. Crystal structure of the C3bot–RalA complex reveals a novel type of action of a bacterial exoenzyme. EMBO J. 24, 3670–3680 (2005) source
The cited paper’s “RalA–C3 complex” section identifies the C3bot interaction site on RalA as a pocket between switch II and helix α3. The citation is attached to the previously described binding site; the proposed effect of small-molecule occupancy is the citing authors’ inference, not a finding attributed to this paper. No page number is available for the decisive passage. (LLM, conf=0.91)
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Lastly, overexpression of a constitutively active (GTP-form22) RalAG23V or RalBG23V, which do not bind these compounds (Extended Data Fig. 3d, 4b), mitigated inhibition of H2122 and H358 cell growth by these compounds (Fig. 3g–j, Extended Data Fig. 6f).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Supportedcites [22] Hinoi, T. et al. Post-translational modifications of Ras and Ral are important for the action of Ral GDP dissociation stimulator. J. Biol. Chem. 271, 19710–19716 (1996) source
The citation is attached to the description of RalG23V as a constitutively active GTP-form mutant, not to the cell-growth results, which cite the citing paper’s own figures. In the Results (page unavailable), Hinoi et al. characterize RalG23V as having reduced GTPase activity that RalGAP does not stimulate; the paper also identifies GTP-bound Ral as the active form. (LLM, conf=0.86)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Ral promotes anchorage-independence1,20, therefore we measured cell growth in soft agar.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Partly supportedcites [1] Lim, K. H. et al. Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr. Biol. 16, 2385–2394 (2006) sourceExperimental — accuracy not yet measured
The passage labeled Abstract reports that suppressing RalA impaired anchorage-independent growth in nine of ten pancreatic cancer cell lines. It also reports that suppressing RalB did not impair soft-agar growth, so the unqualified claim about Ral is broader than this paper supports. (LLM, conf=0.87)
- Supportedcites [20] Balasubramanian, N. et al. RalA–exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling. Curr. Biol. 20, 75–79 (2010) source
The Conclusions state that activated RalA promotes anchorage-independent growth signaling and that the data reveal a mechanism by which it can promote anchorage-independence. The soft-agar measurement is the citing authors’ own next step, not a result attributed to this source. (LLM, conf=0.92)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“RalA and RalB are important drivers of the proliferation, survival and metastasis of multiple human cancers including skin11, lung12, pancreatic1, colon13, prostate14, and bladder15,16.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Partly supportedcites [1] Lim, K. H. et al. Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr. Biol. 16, 2385–2394 (2006) sourceExperimental — accuracy not yet measured
The Results and Discussion (page unavailable) support roles for both RalA and RalB in metastatic growth of pancreatic cancer cells, but distinguish their functions: RalA, not RalB, was required for transformed and tumorigenic growth. The Discussion treats RalB’s role in survival as a possible explanation for its effect on metastasis, not an established finding in these pancreatic cells. This citation is attached to pancreatic cancer, so the other cancer types in the sentence are not assessed here. (LLM, conf=0.88)
- Partly supportedcites [11] Zipfel, P. A. et al. Ral activation promotes melanomagenesis. Oncogene 29, 4859–4864 (2010) sourceExperimental — accuracy not yet measured
The citation is attached to “skin.” In the melanoma findings (indexed as Abstract; page unavailable), knockdown of RalA reduced tumor growth in all tested human melanoma cell lines and knockdown of RalB did so in half, supporting a role in skin-cancer growth. The paper reports no significant change in measured proliferation after either knockdown and does not establish melanoma survival or metastasis effects. (LLM, conf=0.87)
- Partly supportedcites [12] Peschard, P. et al. Genetic deletion of RALA and RALB small GTPases reveals redundant functions in development and tumorigenesis. Curr. Biol. 22, 2063–2068 (2012) sourceExperimental — accuracy not yet measured
The Results and Discussion (page unavailable) reports RNAi studies in human pancreatic cancer cell models suggesting that RALA is required for proliferation and RALB for survival and migration. This supports the pancreatic-cancer portion of the citation, but the paper does not establish metastasis in pancreatic cancer; it describes migration and invasion instead. Its pancreatic mouse-model observation also found that deleting either gene alone did not impair tumor formation. (LLM, conf=0.84)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cell-based secondary screening identified RBC6, 8 and 10 as lead compounds for Ral inhibition”
§ Discovery and characterization of small molecules that target the Ral GTPase > Extended Data
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“BQU57 was tested in vivo at several different doses 10, 20, and 50 mg/kg/d and dose-dependent growth inhibition effects were observed (Fig. 4c).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Compounds RBC6, RBC8 and RBC10 inhibited Ral binding to its effector RalBP1”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, NMR experiments with RalB-GDP demonstrated interactions within the allosteric site.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Probably not a substantial claim. 11
- It may state two separate claims as one. 23
- The quote only partly states this claim. 3
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“Recently, three studies used similar fragment-based small molecule screening to identify compounds that bind sites on the K-Ras surface and block its SOS-mediated activation24–26 suggesting the approach has some promise.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Supportedcites [24] Sun, Q. et al. Discovery of small molecules that bind to K-Ras and inhibit Sos-mediated activation. Angew. Chem. Int. Edn Engl. 51, 6140–6143 (2012) source
The paper reports a fragment-based screen that identified small molecules binding directly to K-Ras (main text, passage 2). Its conclusion states that the compounds block Sos binding and inhibit Sos-mediated nucleotide exchange (passage 1). This citation supports the description of this study as one of the three cited studies; it does not independently establish the total count. (LLM, conf=0.93)
- Supportedcites [25] Maurer, T. et al. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. Proc. Natl Acad. Sci. USA 109, 5299–5304 (2012) source
The Results describe an NMR-based fragment screen that identified compounds binding to a contiguous site on K-Ras. The paper’s opening summary states that selected compounds inhibit SOS-mediated nucleotide exchange and prevent Ras activation. This supports the claim as it applies to this cited study; the paper need not establish the results of the other two studies cited in the sentence. (LLM, conf=0.94)
- Disputedcites [26] Shima, F. et al. In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction. Proc. Natl Acad. Sci. USA 110, 8182–8187 (2013) sourceExperimental — accuracy not yet measured
The Discussion distinguishes this study from compounds that bind K-Ras and inhibit SOS-mediated nucleotide exchange: it says those were reported by Maurer et al., whereas this study's compounds primarily interfere with Ras–effector interactions. The Discovery section describes an in silico docking screen targeting an M-Ras structure, not fragment-based screening for inhibitors of SOS-mediated activation. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The Ras-like GTPases RalA and B are important drivers of tumor growth and metastasis1.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Partly supportedcites [1] Lim, K. H. et al. Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr. Biol. 16, 2385–2394 (2006) sourceExperimental — accuracy not yet measured
The Discussion reports that RalA is critical for tumorigenic growth and that both RalA and RalB contribute to metastatic growth in the pancreatic cancer models studied. It also says RalB was dispensable for tumorigenic growth, so the claim overstates their shared role in tumor growth. (LLM, conf=0.90)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Ral is required for lipid raft exocytosis and spreading of murine embryonic fibroblasts (MEFs) on fibronectin-coated coverslips20.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Partly supportedcites [20] Balasubramanian, N. et al. RalA–exocyst complex regulates integrin-dependent membrane raft exocytosis and growth signaling. Curr. Biol. 20, 75–79 (2010) sourceExperimental — accuracy not yet measured
The Results and Discussion sections on Ral inhibition and RalA/RalB knockdown report that inhibiting RalA delayed lipid-raft return and spreading of WT murine embryonic fibroblasts replated on fibronectin-coated surfaces. The copy identifies those surfaces as fibronectin-coated but does not establish that they were coverslips; it also says spreading was delayed, not completely blocked. No page number is available in the indexed passages. (LLM, conf=0.82)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The IC50 for RBC8 is 3.5 μM in H2122 and 3.4 μM in H358; for BQU57 2.0 μM in H2122 and 1.3 μM in H358.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As shown in Extended Data Fig. 7b–c, the compounds were detected in tumor tissue in vivo.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Molecular docking of RBC6 (c), RBC8 (d), and RBC10 (e) into the target site of RalA-GDP.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Extended Data
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“while compounds RBC5, RBC7, and RBC42 (structures not shown) had no effect and thus served as negative controls.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“RBC8 treatment (50 mg/kg/day) initiated 24 h after inoculation inhibited xenograft tumor growth of human lung cancer cell line H358.”
- Also stated in: § Extended Data · plain
“Tumor volume in the treatment group was statistically different from controls as determined by the Student’s t-test (*p<0.05).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Extended Data
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Extended Data · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“RBC6 and RBC8 are related structures sharing the same bicyclic core (Fig. 1e, f), with specific substitutions giving rise to similar but somewhat different binding orientations in the allosteric binding cavity (Extended Data Fig. 2c–e).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Although our initial library screening was based on RalA structure, the selected compounds also bound RalB, which is not surprising given the similarity of the amino acid sequences and predicted structures.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both RalA and RalB were significantly inhibited by RBC8 (Extended Data Fig. 8a–d) and BQU57 (Fig. 4e) but not by the inactive compound RBC5 (Extended Data Fig. 8e, f).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Attempts to stably overexpress FLAG-RalAG23V or FLAG-RalBG23V in H2122 cells were unsuccessful”
§ Discovery and characterization of small molecules that target the Ral GTPase > METHODS > In vitro growth of human cancer cells
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Colony formation in soft agar showed that the Ral-dependent lines H2122 and H358, but not H460 or Calu6, were sensitive to RBC8 and BQU57 treatment (Fig. 3a, b).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Volumes calculated for this binding site were 175 Å3 for RalA-GDP (Fig. 1b), 155 Å3 for RalA-GNP-exo84 (Fig. 1c), and 116 Å3 for RalA-GNP-sec5 (Fig. 1d).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A second lung cancer line, H358 yielded similar results (Extended Data Fig. 7e).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe quote only partly states this claim.
None of the sources cited for this claim have been checked yet.
In the paper
“In these cells, depletion of RalA by siRNA inhibits spreading of WT MEFs, whereas caveolin deficient (Cav1−/−) MEFs are resistant to RalA depletion.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“H2122/H358 (c) but not H460/Calu6 (d) were sensitive to Ral knockdown.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Extended Data
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Additionally, a Ral pull-down assay using RalBP1 agarose beads8 showed that RBC8 and BQU57 but not RBC5 inhibited both RalA and RalB activation in both the H2122 and H358 cell lines (Extended Data Fig. 5e).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Not checked — no full text of the sourcecites [8] Oxford, G. et al. RalA and RalB: antagonistic relatives in cancer cell migration. Cancer Res. 65, 7111–7120 (2005) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“RBC8 induced chemical shift changes in RalB-GDP but not RalB-GNP, indicating that RBC8 shows selectivity for the GDP bound form of Ral (Extended Data Fig. 3c, d).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When RBC6, RBC8 and RBC10 were tested for effects on cell spreading in WT and Cav1−/− MEFs, inhibition was observed only in the WT MEFs (Fig. 1i, Extended Data Fig. 2b).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Surface model showing absence of the allosteric binding site.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Extended Data
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The majority of the chemical shift changes localized to the allosteric site, consistent with assignment of BQU57 binding to this site based on modeling.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When RBC6, RBC8 and RBC10 were tested for effects on cell spreading in WT and Cav1−/− MEFs, inhibition was observed only in the WT MEFs (Fig. 1i, Extended Data Fig. 2b).”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice were randomized into 6 per group immediately before use (no blinding was done).”
- Also stated in: § Ral activity in tumor xenografts · plain
“mice were randomized into 6 per group (no blinding was done)”
§ Discovery and characterization of small molecules that target the Ral GTPase > METHODS > Tumor growth in mice
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Ral activity in tumor xenografts · plain
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“efforts shifted to target signaling components downstream of Ras such as Raf-MEK-ERK mitogen-activated protein kinases4 and the phosphoinositide 3-kinase-AKT-mTOR pathway5.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Not checked — no full text of the sourcecites [4] Roberts, P. J. & Der, C. J. Targeting the Raf–MEK–ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26, 3291–3310 (2007) source
- Not checked — no full text of the sourcecites [5] Yap, T. A. et al. Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises. Curr. Opin. Pharmacol. 8, 393–412 (2008) source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Though additional medicinal chemistry optimization is required, these Ral inhibitors represent a first generation of valuable tools for elucidating Ral signaling and developing novel agents for cancer therapy.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes? Checkable: unclear✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Similar considerations delayed development of protein kinase inhibitors, and indeed some of the best kinase inhibitors proved to not be competitive with ATP, but are allosteric inhibitors that lock the conformation of kinases such as MEK in a closed state23.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Not checked — no full text of the sourcecites [23] Fang, Z., Grutter, C. & Rauh, D. Strategies for the selective regulation of kinases with allosteric modulators: exploiting exclusive structural features. ACS Chem. Biol. 8, 58–70 (2013) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data provide evidence that RBC8 and BQU57 act specifically through the GDP-bound form of Ral proteins.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“More than one-third of human tumors harbor activating RAS mutations2”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
What the sources say
- Not checked — no full text of the sourcecites [2] Schubbert, S., Shannon, K. & Bollag, G. Hyperactive Ras in developmental disorders and cancer. Nature Rev. Cancer 7, 295–308 (2007) source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For the overexpression experiments, H358 cells stably overexpressing FLAG, FLAG-RalAG23V or FLAG-RalBG23V were generated”
§ Discovery and characterization of small molecules that target the Ral GTPase > METHODS > In vitro growth of human cancer cells
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“One reason for the failures to date to obtain clinically useful inhibitors for Ras and other related GTPases is the highly conserved guanine nucleotide binding site that has high affinity for the guanine nucleotides GDP/GTP present at millimolar concentrations in cells, and would out-compete ligands for this site.”
§ Discovery and characterization of small molecules that target the Ral GTPase > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice were randomized into 6 per group immediately before use (no blinding was done).”
- Also stated in: § Ral activity in tumor xenografts · plain
“mice were randomized into 6 per group (no blinding was done)”
§ Discovery and characterization of small molecules that target the Ral GTPase > METHODS > Tumor growth in mice
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Ral activity in tumor xenografts · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All cell line were fingerprinted by STR profiling and tested for mycoplasma contamination.”
§ Discovery and characterization of small molecules that target the Ral GTPase > METHODS > Materials
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
A third pathway downstream of Ras leading to activation of RalA and RalB has not been targeted to date.
“A third pathway downstream of Ras that leads to activation of the Ras-like small GTPases, RalA and RalB6, has not been targeted to date.”
The paper relies on this without support.
In the ELISA, FLAG-RalA binding to RalBP1 reflects RalA GTP-loading and capacity for effector activation.
“In this assay, the RalA binding reflects its GTP-loading and capacity for effector activation.”
The paper relies on this without support.
The RalB Q72L mutant used for NMR behaves like wild-type RalB in GDP/GNP binding and compound interactions.
“RalB (Q72L mutant) in a pET16b (Novagen) plasmid was a kind gift from Dr. Darerca Owen (Cambridge University).”
The paper relies on this without support.
The allosteric binding site in RalA-GDP is structurally conserved in RalB-GDP sufficiently for homology modeling and mapping of NMR chemical shift changes.
“Because no RalB-GDP crystal structure is available, instead a homology model was generated based on the similarity to RalA-GDP, and the residues that displayed chemical shift changes in response to the compounds were mapped onto this model (Fig. 2e).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“RBC8-a selective small-molecule inhibitor of Ral that binds to GDP-bound Ral and prevents its activation by blocking conversion to the GTP-bound active state 34 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [34]
Citations
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Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer
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Hyperactive Ras in developmental disorders and cancer
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Discovery of Small Molecules that Bind to K‐Ras and Inhibit Sos‐Mediated Activation
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Activation of RalA is critical for Ras-induced tumorigenesis of human cells
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Items 101–150 of 150
Antitumor Effects of Ral-GTPases Downregulation in Glioblastoma
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Exploring Covalent Bond Formation at Tyr‐82 for Inhibition of Ral GTPase Activation
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Ral GTPases are critical regulators of spinal cord myelination and homeostasis
DeGeer, J., Dätwyler, A. L., Rickenbach, C., Ommer, A., Gerber, D., Fimiani, C., Gerber, J., Pereira, J. A., & Suter, U. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111413 · Cited by 5
RAS: Circuitry and therapeutic targeting
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KRAS et adénocarcinome bronchique. Entre déceptions et espoirs
Guibert, N. M., Ilié, M., Léna, H., Didier, A. P., Hofman, P. M., & Mazières, J. (2015) · Revue des Maladies Respiratoires · doi:10.1016/j.rmr.2015.05.012 · Cited by 4
Protein–Protein Interaction Inhibitors in Cancer
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Self-citationResearch progress of direct and indirect KRAS-targeting protein degraders in KRAS-mutant cancers
Jiang, L., Chen, Y., Zhao, J., Zhou, L., Zhou, Q., Jiang, H., Lou, D., Huang, W., & Zhang, Y. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.109161 · Cited by 4
Identification of RALA as a Therapeutic Target and Prognostic Predictor of Osteosarcoma
Fan, G., Zhu, Y., Zhu, H., Yu, L., Wang, Z., Zhai, C., Zhou, G., Zhao, J., & Wang, Y. (2023) · BioMed Research International · doi:10.1155/2023/1150768 · Cited by 3
The RAL Small G Proteins Are Clinically Relevant Targets in Triple Negative Breast Cancer
Han, D. K. M., Spehar, J. M., Richardson, D. S., Leelananda, S. P., Chakravarthy, P. A., Grecco, S., Reardon, J. J., Stover, D. G., Bennett, C. E., Sizemore, G. M., et al. (2024) · Cancers · doi:10.3390/cancers16173043 · Cited by 3
Ral GTPases promote metastasis by controlling biogenesis and organ colonization of exosomesPreprint
Ghoroghi, S., Mary, B., Larnicol, A., Klein, A., Osmani, N., Busnelli, I., Delalande, F., Paul, N., Halary, S., Gros, F., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.10.196691 · Cited by 3
Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover
Feng, X., Zhang, S., Wang, Y., Kurlagunda, T., Sit, A., Jaishankar, P., Yang, P., Sakane, S., Park, S. Y., Wisessaowapak, C., et al. (2026) · Nature · doi:10.1038/s41586-026-10697-z · Cited by 2
An evolutionarily conserved salt bridge stabilizes the active site for GTP hydrolysis in Rho GTPases
Marcus, K., Schwabe, M., Knihtila, R., & Mattos, C. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.111260 · Cited by 2
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GTPase Ral—a new tumour target
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The Many Roles of Ral GTPases in Ras-Driven Cancer
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Small‐Molecule KRAS Inhibitors by Tyrosine Covalent Bond Formation
Landgraf, A. D., Brenner, R., Ghozayel, M. K., Bum‐Erdene, K., González-Gutiérrez, G., & Meroueh, S. O. (2025) · ChemMedChem · doi:10.1002/cmdc.202400624 · Cited by 1
Self-citationCyclized Peptide Inhibitors of the Small G Protein Cdc42 Mimic Binding of Effector Proteins
Murphy, N. P., Tetley, G. J. N., Revell, J. D., Mott, H. R., & Owen, D. (2026) · Biochemistry · doi:10.1021/acs.biochem.5c00616 · Cited by 1
M-Sec promotes the production of infectious HIV-1 virus through the exocyst complex in macrophages
Mahmoud, R. M., Hiyoshi, M., Abdelnaser, R. A., Monde, K., Monde, N., Koma, T., Mizuno, H., Habash, S. A., Takahashi, N., Maeda, Y., et al. (2026) · PLoS Pathogens · doi:10.1371/journal.ppat.1013717 · Cited by 1
One step closer to targeting RAS
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Self-citationGrowing Popularity of Ultrasensitive Microcalorimetry
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Regulation of Ras p21 and RalA GTPases activity by quinine in mammary epithelial cells
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Targeting der kleinen GTPasen über ihre regulatorischen Proteine
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Targeting the Ras-Ral effector pathway for cancer treatment
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Ras and Ras Signaling as a Therapeutic Target in Cancer
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A RalA between high-fat diet and mitochondrial shape
Zambello, L., & Scorrano, L. (2024) · Nature Metabolism · doi:10.1038/s42255-023-00969-7
Mediating kinase activity in Ras-mutant cancer: potential for an individualised approach?
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TNFAIP2 increases macrophage response to CSF-1 through multiple effects on CSF-1 receptor
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Metadata
- Authors
- Yan, C., Liu, D., Li, L., Wempe, M. F., Guin, S., Khanna, M., Meier, J., Hoffman, B., Owens, C., Wysoczynski, C. L., Nitz, M. D., Knabe, W. E., Ahmed, M., Brautigan, D. L., Paschal, B. M., Schwartz, M. A., Jones, D. N. M., Ross, D., Meroueh, S. O., & Theodorescu, D.
- Affiliations
- University of Colorado Anschutz (US)
- Indiana University Indianapolis (US)
- University of Virginia (US)
- Yale University (US)
- Indiana University School of Medicine (US)
- University of Colorado Cancer Center (US)
- Corresponding author
- Theodorescu, Dan
- ORCID
- Venue
- Nature
- Published
- 2014-09-14
- Volume
- 515
- Issue
- 7527
- Pages
- 443-447
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4351747
- OpenAlex
- W2076865122
- Semantic Scholar
- 4d374733558595cd1d9f434c6874e22f2b6e1d3c
- Cited by
- 150
- References
- 34
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 6 · 2023: 8 · 2022: 10 · 2021: 13 · 2020: 18 · 2019: 12 · 2018: 12 · 2017: 7 · 2016: 21 · 2015: 22 · 2014: 2
- FWCI
- 7.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- PMC
- Funders
- National Institutes of Health (UL1TR001082)
- National Heart, Lung, and Blood Institute (R01HL075092)
- National Cancer Institute (CA 075115, CA 091846, P01CA104106, R01CA075115, P50CA091846, CA 104106, R29CA075115, P30CA046934, P30CA044579)
- National Institute of General Medical Sciences (T32GM007635, GM-47214, R01GM047214)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- Ral GTPase, small molecule inhibitors, RalA, RalB, Ras signaling, RALBP1, structure-based drug design, virtual screening, anchorage-independent growth, cancer therapy
- MeSH terms
- Animals, Computer Simulation, Drug Screening Assays, Antitumor, Female, Humans, Models, Molecular, Neoplasms, Protein Binding, Substrate Specificity, Signal Transduction, ATP-Binding Cassette Transporters, ras Proteins, GTPase-Activating Proteins, ral GTP-Binding Proteins, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, Small Molecule Libraries, Molecular Targeted Therapy
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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