RHEB

Summary

RHEB (Ras homolog, mTORC1 binding, HGNC:10011) is a protein-coding gene on chromosome 7q36.1, encoding GTP-binding protein Rheb (Q15382). Small GTPase that acts as an allosteric activator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth. It is a selective cancer dependency (DepMap: 40.6% of cell lines).

This gene is a member of the small GTPase superfamily and encodes a lipid-anchored, cell membrane protein with five repeats of the RAS-related GTP-binding region. This protein is vital in regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway. The protein has GTPase activity and shuttles between a GDP-bound form and a GTP-bound form, and farnesylation of the protein is required for this activity. Three pseudogenes have been mapped, two on chromosome 10 and one on chromosome 22.

Source: NCBI Gene 6009 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 34 total — 6 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 40.6% of screened cell lines
• MANE Select transcript: NM_005614

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10011
Approved symbol	RHEB
Name	Ras homolog, mTORC1 binding
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000106615
Ensembl biotype	protein_coding
OMIM	601293
Entrez	6009

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000262187, ENST00000470072, ENST00000470370, ENST00000472642, ENST00000478470, ENST00000482053, ENST00000496004, ENST00000876654, ENST00000924902

RefSeq mRNA: 1 — MANE Select: NM_005614 NM_005614

CCDS: CCDS5927

Canonical transcript exons

ENST00000262187 — 8 exons

Exon	Start	End
ENSE00001200523	151519460	151519895
ENSE00001321653	151466012	151467211
ENSE00003459693	151484737	151484804
ENSE00003462668	151470571	151470652
ENSE00003464369	151490943	151491014
ENSE00003489666	151471394	151471441
ENSE00003529508	151477333	151477415
ENSE00003576426	151471549	151471605

Expression profiles

Bgee: expression breadth ubiquitous, 218 present calls, max score 99.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.7442 / max 108.5483, expressed in 1673 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86907	1.8292	1252
86909	1.5371	933
86908	0.7085	423
86905	0.5520	222
86906	0.0910	45
86902	0.0194	9
86903	0.0070	2

Top tissues by expression

252 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.19	gold quality
embryo	UBERON:0000922	98.55	gold quality
ganglionic eminence	UBERON:0004023	98.55	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.52	gold quality
lower esophagus	UBERON:0013473	98.51	gold quality
smooth muscle tissue	UBERON:0001135	98.45	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.41	gold quality
mucosa of stomach	UBERON:0001199	98.38	gold quality
anterior cingulate cortex	UBERON:0009835	98.32	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.32	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.22	gold quality
left adrenal gland cortex	UBERON:0035825	98.16	gold quality
left adrenal gland	UBERON:0001234	98.15	gold quality
right frontal lobe	UBERON:0002810	98.14	gold quality
body of uterus	UBERON:0009853	98.12	gold quality
right adrenal gland cortex	UBERON:0035827	98.10	gold quality
left uterine tube	UBERON:0001303	98.07	gold quality
popliteal artery	UBERON:0002250	98.05	gold quality
tibial artery	UBERON:0007610	98.05	gold quality
right adrenal gland	UBERON:0001233	97.99	gold quality
tibial nerve	UBERON:0001323	97.99	gold quality
right atrium auricular region	UBERON:0006631	97.99	gold quality
right lung	UBERON:0002167	97.96	gold quality
islet of Langerhans	UBERON:0000006	97.95	gold quality
left coronary artery	UBERON:0001626	97.88	gold quality
ascending aorta	UBERON:0001496	97.85	gold quality
adenohypophysis	UBERON:0002196	97.85	gold quality
thoracic aorta	UBERON:0001515	97.83	gold quality
aorta	UBERON:0000947	97.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.77	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	65.12
E-GEOD-137537	yes	30.09
E-MTAB-7316	yes	23.43
E-CURD-46	yes	10.33
E-CURD-114	yes	10.18
E-HCAD-13	yes	7.32
E-GEOD-81383	no	353.64
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

74 targeting RHEB, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-142-3P	99.62	71.30	974
HSA-MIR-7112-5P	99.59	65.76	104
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-6733-3P	99.54	67.80	1281

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 40.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner (PMID:12842888)
• transient expression of the wild type Rheb1 or Rheb2 causes activation of p70S6K, while expression of Rheb1D60K mutant results in inhibition of basal level activity of p70S6K (PMID:12869548)
• Rheb acts downstream of TSC1/TSC2 and upstream of mTOR to regulate cell growth (PMID:12869586)
• Rheb has a role in regulation of B-Raf kinase activity along with tuberin but without involvement of mTOR (PMID:15150271)
• To investigate the function of TSC2 and Rheb in mTOR signaling, we analyzed the TSC2-stimulated Rheb GTPase activity. (PMID:15340059)
• The GTPase domain of human Rheb (hRheb) has been recombinantly expressed in Escherichia coli, purified and cocrystallized in complexes with GDP, GTP and GppNHp. (PMID:15388940)
• Rheb forms a new group of the Ras/Rap subfamily and uses a novel GTP hydrolysis mechanism that utilizes Asn1643 of the tuberous sclerosis complex 2 GTPase-activating protein domain instead of Gln64 of Rheb as the catalytic residue (PMID:15728574)
• results suggest that Rheb regulates endocytic trafficking pathway independent of the previously identified mTOR pathway. (PMID:15809346)
• The target of rapamycin (TOR) complex 1 is a direct target of Rheb-GTP, whose binding enables activation of the TOR kinase. (PMID:15854902)
• binding of Rheb to endogenous and recombinant mTOR is reversibly inhibited by withdrawal of all extracellular amino acids or just leucine (PMID:15878852)
• Data show that the farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. (PMID:16006564)
• Data show that Rheb like-1 protein (RhebL1) rescues mTOR signaling during nutrient withdrawal, and identify critical residues in Rheb and RhebL1 which are required for their efficient activation of mTOR signaling. (PMID:16098514)
• Our results demonstrate that Ebp1 is a new dsRNA-binding protein that acts as a cellular inhibitor of eIF2alpha phosphorylation suggesting that it could be involved in protein translation control (PMID:16631613)
• Rheb has a central role in the regulation of the Ras/B-Raf/C-Raf/MEK signaling network (PMID:16803888)
• The TSC/Rheb/mTOR pathway plays a critical role in the regulation of E(2)-induced proliferation. (PMID:17018601)
• Rheb signaling to mTOR in vivo requires a Rheb switch 2-dependent interaction with an element other than the three known polypeptide components of TOR complex 1 (PMID:17470430)
• Bnip3, a hypoxia-inducible Bcl-2 homology 3 domain-containing protein, directly binds Rheb and inhibits the mTOR pathway. (PMID:17928295)
• findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability (PMID:17991864)
• RHEB could be used cytopathologically to distinguish fibroadenoma from malignant breast carcinomas as a secondary diagnostic tool. (PMID:18324915)
• Constitutively active Rheb induces oncogenic transformation. (PMID:18521078)
• PLD1 is required for Rheb activation of the mTOR pathway. (PMID:18550814)
• ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo (PMID:18650380)
• FKBP38 is a bona fide effector of Rheb and the ability to interact with FKBP38 is important for Rheb as an activator of mTOR (PMID:18658153)
• Rheb overexpression is associated with prostate cancer (PMID:18708577)
• RHEB overexpression accelerates lymphomagenesis in the Eu-myc model (PMID:18708578)
• Inhibition of PI3K or mTOR reduced the level of Rap1B, which acts downstream of Rheb and mTOR. The ubiquitin E3 ligase Smurf2 mediates the restriction of Rap1B by initiating its degradation. (PMID:18842593)
• RalGDS and RalA act downstream of Rheb and that RalA activation is a crucial step in nutrient-induced mTORC1 activation (PMID:18948269)
• FKBP38 is not the long-sought Rheb effector linking Rheb to mTORC1 activation. (PMID:19222999)
• TCTP interacts with hRheb and accelerates its GDP release in vitro. (PMID:19570981)
• Backbone and side chain assignments were obtained from three dimensional NMR spectra. (PMID:19636822)
• Data inidicate that FTS could be a promising treatment for Rheb- and mTOR-dependent cancers. (PMID:19838215)
• Rheb GTPase controls apoptosis by regulating interaction of FKBP38 with Bcl-2 and Bcl-XL (PMID:20048149)
• integrity of late endosomes is essential for amino acid- and insulin-stimulated mTORC1 signaling and blocking the early/late endosomal conversion prevents mTOR from interacting with Rheb in the late endosomal compartment (PMID:20053679)
• Rheb potentiates proliferation of prostate cancer cells (PMID:20127734)
• Findings illustrate a mechanism for the cardioprotective effects of lovastatin through inhibition of Rheb and mTORC1 and promotion of a differentiated vascular smooth muscle cell phenotype. (PMID:20375271)
• RHEB is an MTOR activator that facilitates multistage carcinogenesis through induction of multiple oncogenic mechanisms (PMID:20388784)
• Results suggest that Rheb is a critical target for farnesyltransferase inhibitor therapy in non-small cell lung cancer cells. (PMID:20554106)
• Ras homolog enriched in brain (Rheb) enhances apoptotic signaling (PMID:20685651)
• The activating transcription factor (ATF)6alpha/Rheb pathway is altered in Huntington’s disease, as the decrease in ATF6alpha processing is accompanied by a decrease in the accumulation of Rheb. (PMID:20732420)
• Rheb controls proliferation of TSC2-deficient cells by a mechanism that involves regulation of AMPK and p27, and that Rheb is a potential target for TSC/LAM therapy. (PMID:20818424)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rheb	ENSMUSG00000028945
rattus_norvegicus	Rheb	ENSRNOG00000050578

Paralogs (35): RALA (ENSG00000006451), REM1 (ENSG00000088320), RASL10A (ENSG00000100276), RASD2 (ENSG00000100302), RASL12 (ENSG00000103710), RASD1 (ENSG00000108551), RERGL (ENSG00000111404), RAP1A (ENSG00000116473), RASL11A (ENSG00000122035), RAP2C (ENSG00000123728), RAP2A (ENSG00000125249), RRAS (ENSG00000126458), RAP1B (ENSG00000127314), RASL11B (ENSG00000128045), KRAS (ENSG00000133703), RRAS2 (ENSG00000133818), RERG (ENSG00000134533), REM2 (ENSG00000139890), RIT1 (ENSG00000143622), RALB (ENSG00000144118), RIT2 (ENSG00000152214), MRAS (ENSG00000158186), DIRAS3 (ENSG00000162595), GEM (ENSG00000164949), DIRAS2 (ENSG00000165023), RRAD (ENSG00000166592), RHEBL1 (ENSG00000167550), NKIRAS2 (ENSG00000168256), HRAS (ENSG00000174775), DIRAS1 (ENSG00000176490), RAP2B (ENSG00000181467), ERAS (ENSG00000187682), NKIRAS1 (ENSG00000197885), NRAS (ENSG00000213281), RASL10B (ENSG00000270885)

Protein

Protein identifiers

GTP-binding protein Rheb — Q15382 (reviewed: Q15382)

Alternative names: Ras homolog enriched in brain

All UniProt accessions (5): Q15382, A0A090N900, C9J469, C9J931, F8WBL3

UniProt curated annotations — full annotation on UniProt →

Function. Small GTPase that acts as an allosteric activator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth. In response to nutrients, growth factors or amino acids, specifically activates the protein kinase activity of MTOR, the catalytic component of the mTORC1 complex: acts by causing a conformational change that allows the alignment of residues in the active site of MTOR, thereby enhancing the phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1). RHEB is also required for localization of the TSC-TBC complex to lysosomal membranes. In response to starvation, RHEB is inactivated by the TSC-TBC complex, preventing activation of mTORC1. Has low intrinsic GTPase activity.

Subunit / interactions. Associates with the mTORC1 complex (MTOR, MLST8 and RPTOR) in a guanyl nucleotide-independent manner. Interacts with TSC2. Interacts with MCRS1; the interaction maintains RHEB at the lysosome in its active GTP-bound form and prevents its interaction with the mTORC1 complex inhibitor TSC2, ensuring activation of the mTORC1 complex by RHEB. Interacts (when prenylated) with PDE6D; this promotes release from membranes.

Subcellular location. Endomembrane system. Lysosome membrane. Golgi apparatus membrane. Endoplasmic reticulum membrane. Cytoplasm. Cytosol.

Tissue specificity. Ubiquitous. Highest levels observed in skeletal and cardiac muscle.

Post-translational modifications. Farnesylation is important for efficiently activating mTORC1-mediated signaling. Polyubiquitinated in response to amino acid, promoting its interaction with MTOR and mTORC1 activation. Deubiquitination by ATXN3 promotes recruitment of the TSC-TBC complex and RHEB inactivation by TSC2. Monoubiquitinated at Lys-8 by RNF152, promoting its association with the TSC-TBC complex. Deubiquitinated at Lys-8 by USP4, promoting mTORC1 activation. Phosphorylation by MAPKAPK5 impairs GTP-binding and inactivation.

Activity regulation. Alternates between an inactive form bound to GDP and an active form bound to GTP. Inactivated by the TSC-TBC complex via the GTPase activating protein (GAP) domain of TSC2. Autoinhibited by Tyr-35, which constrains the active site conformation, restricting the access of the catalytic Asp-65 to the nucleotide-binding pocket. Specifically inhibited by NR1 (4-bromo-6-(3,4-dichlorophenylthio)-1-(4-(dimethylcarbamoyl)benzyl)-1H-indole-2-carboxylic acid).

Miscellaneous. The conserved catalytic Gln-64 found in other Ras-like GTPases does not seem to be involved in GTP hydrolysis in RHEB.

Similarity. Belongs to the small GTPase superfamily. Rheb family.

RefSeq proteins (1): NP_005605* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR020849	Small_GTPase_Ras-type	Family
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071

Enzyme classification (BRENDA):

• EC 3.6.5.2 — small monomeric GTPase (BRENDA: 49 organisms, 138 substrates, 55 inhibitors, 5 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	—	0

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (73 total): mutagenesis site 26, binding site 24, strand 7, helix 6, modified residue 2, chain 1, propeptide 1, short sequence motif 1, site 1, lipid moiety-binding region 1, cross-link 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
6BSX	X-RAY DIFFRACTION	1.65
3T5G	X-RAY DIFFRACTION	1.7
1XTQ	X-RAY DIFFRACTION	2
3SEA	X-RAY DIFFRACTION	2
7BTD	X-RAY DIFFRACTION	2
5YXH	X-RAY DIFFRACTION	2.04
7BTC	X-RAY DIFFRACTION	2.1
6BT0	X-RAY DIFFRACTION	2.6
7BTA	X-RAY DIFFRACTION	2.6
1XTR	X-RAY DIFFRACTION	2.65
1XTS	X-RAY DIFFRACTION	2.8
9ED7	ELECTRON MICROSCOPY	3.16
9ED4	ELECTRON MICROSCOPY	3.23
9ED8	ELECTRON MICROSCOPY	3.61
6BCU	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15382-F1	92.93	0.85

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 35 (important for autoinhibition of gtpase activity)

Ligand- & substrate-binding residues (24): 20; 20; 20; 21; 21; 32; 32; 33; 35; 38; 38; 119 …

Post-translational modifications (4): 130, 181, 181, 8

Mutagenesis-validated functional residues (26):

Position	Phenotype
8	decreased ubiquitination by rnf152. does not affect polyubiquitination in response to amino acids.
15	partially resistant to inactivation by tsc1-tsc2.
20	deficient in guanine nucleotide binding. unable to rescue rps6kb1 from inactivation by amino-acid withdrawal. reduces af
35	increased gtpase activity; insensitive to tsc2 regulation, leading to impaired regulation of mtorc1 signaling.
35	dominant mutant, which can activate mtorc1 in both gdp- and gtp-bound forms.
38	slightly impairs signaling through mtorc1, but still binds guanine nucleotides normally.
39	impairs rps6kb1 activation, but still binds guanine nucleotides normally. slightly reduces interaction with mcrs1.
40	no effect.
41	impairs interaction with mtor. impairs signaling through mtorc1, but still binds guanine nucleotides normally.
43	no effect.
46	causes slight reduction in rps6kb1 activation.
48	causes slightly reduced phosphorylation of eif4ebp1.
49	causes slightly reduced phosphorylation of eif4ebp1.
53	causes slightly reduced phosphorylation of eif4ebp1.
54	partially deficient in guanine nucleotide binding. fully impairs eif4ebp1 phosphorylation and rps6kb1 activation.
56	partially deficient in guanine nucleotide binding. fully impairs eif4ebp1 phosphorylation and rps6kb1 activation.
60	unstable protein, which cannot load gtp.
60	deficient in guanine nucleotide binding. unable to rescue rps6kb1 from inactivation by amino-acid withdrawal. significan
60	unable to bind mg(2+), preventing nucleotide-binding.
64	has a higher basal gtpase level, however, is still sensitive to tsc2 gap activity. increases affinity for mcrs1.
65	renders rheb insensitive to tsc2 regulation, leading to impaired regulation of mtorc1 signaling.
109	decreased ubiquitination in response to amino acids; when associated with r-135, r-151 and r-178.
135	decreased ubiquitination in response to amino acids; when associated with r-109, r-151 and r-178.
151	decreased ubiquitination in response to amino acids; when associated with r-109, r-135 and r-178.
178	decreased ubiquitination in response to amino acids; when associated with r-109, r-135 and r-151.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-165159	MTOR signalling
R-HSA-166208	mTORC1-mediated signalling
R-HSA-380972	Energy dependent regulation of mTOR by LKB1-AMPK
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-8943724	Regulation of PTEN gene transcription
R-HSA-9639288	Amino acids regulate mTORC1

MSigDB gene sets: 316 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOCC_VACUOLAR_MEMBRANE, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GOBP_POSITIVE_REGULATION_OF_GLIAL_CELL_DIFFERENTIATION, GOBP_TYPE_B_PANCREATIC_CELL_DEVELOPMENT, MORF_RAD21, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_MACROAUTOPHAGY

GO Biological Process (19): signal transduction (GO:0007165), small GTPase-mediated signal transduction (GO:0007264), response to virus (GO:0009615), regulation of macroautophagy (GO:0016241), cellular response to nutrient levels (GO:0031669), positive regulation of TOR signaling (GO:0032008), oligodendrocyte differentiation (GO:0048709), positive regulation of oligodendrocyte differentiation (GO:0048714), regulation of cell cycle (GO:0051726), negative regulation of cold-induced thermogenesis (GO:0120163), positive regulation of TORC1 signaling (GO:1904263), regulation of type B pancreatic cell development (GO:2000074), autophagosome assembly (GO:0000045), cytoplasmic translation (GO:0002181), negative regulation of autophagy (GO:0010507), regulation of TOR signaling (GO:0032006), TORC1 signaling (GO:0038202), negative regulation of translational initiation (GO:0045947), positive regulation of translational initiation (GO:0045948)

GO Molecular Function (11): magnesium ion binding (GO:0000287), GTPase activity (GO:0003924), GTP binding (GO:0005525), GDP binding (GO:0019003), protein kinase binding (GO:0019901), protein kinase activator activity (GO:0030295), protein serine/threonine kinase activator activity (GO:0043539), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (15): Golgi membrane (GO:0000139), spliceosomal complex (GO:0005681), lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), endomembrane system (GO:0012505), postsynaptic density (GO:0014069), membrane (GO:0016020), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), lysosome (GO:0005764), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
MTOR signalling	2
Autophagy	1
Signal Transduction	1
Transcriptional Regulation by TP53	1
PTEN Regulation	1
Cellular response to starvation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
TOR signaling	3
cytoplasm	3
regulation of cellular process	2
cellular response to stimulus	2
regulation of autophagy	2
translational initiation	2
regulation of translational initiation	2
guanyl ribonucleotide binding	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cell communication	1
cellular process	1
signaling	1
intracellular signaling cassette	1
response to other organism	1
macroautophagy	1
response to nutrient levels	1
regulation of TOR signaling	1
positive regulation of intracellular signal transduction	1
central nervous system development	1
glial cell differentiation	1
positive regulation of glial cell differentiation	1
oligodendrocyte differentiation	1
regulation of oligodendrocyte differentiation	1
cell cycle	1
negative regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
positive regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
type B pancreatic cell development	1
regulation of cell development	1
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1

Protein interactions and networks

STRING

3439 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHEB	RPTOR	Q8N122	998
RHEB	TSC2	P49815	997
RHEB	MTOR	P42345	997
RHEB	MLST8	Q9BVC4	984
RHEB	BNIP3	Q12983	981
RHEB	AKT1S1	Q96B36	980
RHEB	TSC1	Q92574	977
RHEB	BNIP3L	O60238	967
RHEB	GAPDH	P00354	945
RHEB	RRAGC	Q9HB90	942
RHEB	RRAGB	Q5VZM2	940
RHEB	RRAGA	Q7L523	939
RHEB	FKBP8	Q14318	931
RHEB	RRAGD	Q9NQL2	928
RHEB	RPS6KB1	P23443	923

IntAct

127 interactions, top by confidence:

A	B	Type	Score
RELL2	OXSR1	psi-mi:“MI:0914”(association)	0.830
RAC1	RAP1GDS1	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LAMP2	RHEB	psi-mi:“MI:0915”(physical association)	0.670
EIF4EBP1	MTOR	psi-mi:“MI:0915”(physical association)	0.660
RHEB	MTOR	psi-mi:“MI:0915”(physical association)	0.590
MTOR	RHEB	psi-mi:“MI:0915”(physical association)	0.590
RHEB	TPT1	psi-mi:“MI:0407”(direct interaction)	0.560
RHEB	APPBP2	psi-mi:“MI:0915”(physical association)	0.560
CASP6	RHEB	psi-mi:“MI:0915”(physical association)	0.560
RHEB	CCK	psi-mi:“MI:0915”(physical association)	0.560
RHEB		psi-mi:“MI:0915”(physical association)	0.560
RHEB	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
GRIN2C	RHEB	psi-mi:“MI:0915”(physical association)	0.560
HIP1	RHEB	psi-mi:“MI:0915”(physical association)	0.560
RAN	RHEB	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	RHEB	psi-mi:“MI:0915”(physical association)	0.560
PRPF40A	RHEB	psi-mi:“MI:0915”(physical association)	0.560
CCK	RHEB	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (173): PLD1 (Affinity Capture-Western), MTOR (Affinity Capture-Western), RHEB (Reconstituted Complex), RHEB (Biochemical Activity), PLD1 (Biochemical Activity), RHEB (Affinity Capture-Western), RHEB (Affinity Capture-MS), RHEB (Affinity Capture-MS), RHEB (Affinity Capture-MS), RHEB (Co-fractionation), RHEB (Co-fractionation), RHEB (Two-hybrid), RPTOR (Co-localization), RHEB (Affinity Capture-MS), RHEB (Affinity Capture-MS)

ESM2 similar proteins: A1XQR9, B5FYY5, F1QGW6, F6RQL9, O35900, O93377, P41091, P61599, P61600, P62308, P62309, P62310, P62311, P81795, Q09028, Q0VC00, Q13126, Q13888, Q15382, Q17QI2, Q2KHU8, Q2PFM2, Q2TBV5, Q32PE9, Q3MHL3, Q3ZBL0, Q4KLK9, Q58ED9, Q5M7K4, Q5R797, Q5RF92, Q5ZJQ7, Q60972, Q62639, Q6INH0, Q6P1K8, Q6P3H7, Q6P632, Q7ZUG0, Q7ZXR3

Diamond homologs: A1DZY4, A6QP66, A8NU18, C4YKT4, O08989, O14807, O35929, O88667, O93856, O94363, P01119, P03967, P08645, P08647, P0CY32, P10114, P10536, P11233, P11234, P15064, P17609, P22124, P22126, P22278, P22279, P22280, P28775, P32254, P36860, P36863, P48555, P59279, P61105, P61225, P61226, P61227, P62070, P62071, P63320, P63321

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
TSC2	“down-regulates activity”	RHEB	“gtpase-activating protein”
RHEB	“up-regulates activity”	MTOR	binding
BNIP3	down-regulates	RHEB	binding
RHEB	down-regulates	FKBP8	binding
TSC1	“down-regulates activity”	RHEB	binding
RHEB	up-regulates	PLD1	binding
RHEB	“up-regulates activity”	mTORC1
RHEB	“down-regulates activity”	FKBP8	“gtpase-activating protein”
TSC	“down-regulates activity”	RHEB	“gtpase-activating protein”
MAPKAPK5	“down-regulates activity”	RHEB	phosphorylation
RHEB	“down-regulates activity”	EIF2AK3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 110 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Constitutive Signaling by Aberrant PI3K in Cancer	6	10.6×	3e-03
PIP3 activates AKT signaling	8	7.4×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of stress fiber assembly	5	15.9×	7e-03
cellular response to amino acid stimulus	5	15.6×	7e-03
positive regulation of ERK1 and ERK2 cascade	8	7.0×	7e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	8	6.4×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

34 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	16
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1068862	NC_000007.13:g.(?150642443)(151385353_?)del	Pathogenic
1702651	NM_005614.4(RHEB):c.104A>C (p.Tyr35Ser)	Pathogenic
3238630	NM_005614.4(RHEB):c.104_105delinsTA (p.Tyr35Leu)	Pathogenic
376516	NM_005614.4(RHEB):c.104A>G (p.Tyr35Cys)	Pathogenic
4077173	NM_005614.4(RHEB):c.110C>T (p.Pro37Leu)	Pathogenic
4088138	NM_005614.4(RHEB):c.202T>C (p.Ser68Pro)	Pathogenic
545666	NM_005614.4(RHEB):c.119A>T (p.Glu40Val)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1209 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:151471414:C:A	K120N	1.000
7:151471414:C:G	K120N	1.000
7:151484750:T:C	D60G	1.000
7:151490974:A:C	F31L	1.000
7:151490974:A:T	F31L	1.000
7:151490976:A:G	F31L	1.000
7:151519475:C:G	G13R	1.000
7:151470584:G:T	A150D	0.999
7:151470621:C:G	A138P	0.999
7:151470633:C:A	G134W	0.999
7:151471406:A:G	L123P	0.999
7:151471409:T:G	D122A	0.999
7:151471416:T:C	K120E	0.999
7:151471421:C:T	G118E	0.999
7:151471422:C:A	G118W	0.999
7:151471424:A:T	V117D	0.999
7:151471605:A:C	S92R	0.999
7:151471605:A:T	S92R	0.999
7:151477334:T:G	S92R	0.999
7:151477343:A:G	S89P	0.999
7:151477352:A:G	S86P	0.999
7:151484741:C:T	G63E	0.999
7:151484742:C:A	G63W	0.999
7:151484742:C:G	G63R	0.999
7:151484742:C:T	G63R	0.999
7:151484744:G:T	A62D	0.999
7:151484749:G:C	D60E	0.999
7:151484749:G:T	D60E	0.999
7:151484750:T:A	D60V	0.999
7:151484750:T:G	D60A	0.999

dbSNP variants (sampled 300 via entrez): RS1000119426 (7:151476520 C>A), RS1000133483 (7:151495701 A>C), RS1000136631 (7:151485754 T>G), RS1000172151 (7:151476825 A>C), RS1000215601 (7:151510723 A>G), RS1000290831 (7:151521360 G>A,T), RS1000308691 (7:151470268 T>C,G), RS1000319583 (7:151467773 G>A), RS1000350719 (7:151467476 C>G), RS1000398515 (7:151482749 A>G), RS1000429165 (7:151515910 G>T), RS1000466496 (7:151486074 C>G,T), RS1000485867 (7:151495445 G>A), RS1000675200 (7:151521566 G>A,C), RS1000687256 (7:151497532 C>T)

Disease associations

OMIM: gene MIM:601293 | disease phenotypes: MIM:607341

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (5): long QT syndrome (MONDO:0002442), intellectual disability (MONDO:0001071), isolated focal cortical dysplasia type II (MONDO:0011818), hemimegalencephaly (MONDO:0020492), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (3): Isolated focal cortical dysplasia type II (Orphanet:268994), Hemimegalencephaly (Orphanet:99802), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005351_5	Carboplatin disposition in epthelial ovarian cancer	6.000000e-06
GCST009391_269	Metabolite levels	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010427	triacylglycerol 54:9 measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D065705	Hemimegalencephaly	C05.660.207.536.500; C10.500.507.400.249.500; C16.131.621.207.532.500; C16.131.666.507.400.249.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C537067	Focal cortical dysplasia of Taylor (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3108656 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

Binding affinities (BindingDB)

36 measured of 37 human assays (37 total across all organisms); most potent 36 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
trans-(1R,3R)-3-[(5,6-dichloro-2-pyridin-4-yl-1H-benzimidazol-4-yl)oxymethyl]cyclohexan-1-ol	IC50	51500 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
cis-(1R,3S)-3-[(5,6-dichloro-2-pyridin-4-yl-1H-benzimidazol-4-yl)oxymethyl]cyclohexan-1-ol	IC50	51500 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
1-(6-chloro-4-phenoxy-1H-indol-2-yl)-2-trimethylsilylethanol	IC50	55000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
1-(6-chloro-4-phenoxy-1H-indol-2-yl)ethanol	IC50	55000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
1-(4-bromo-6-phenoxy-1H-indol-2-yl)ethanol	IC50	55000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
1-[5,6-dichloro-4-(cyclohexylmethoxy)-1H-benzimidazol-2-yl]ethane-1,2-diol	IC50	55000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
N-[(1R,2S)-2-[[5,6-dichloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]cyclohexyl]acetamide	IC50	55000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
cis-(1S,2R)-2-[[5,6-dichloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]cyclohexan-1-ol	IC50	55000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
cis-(1S,2R)-2-[[5,6-dichloro-2-(hydroxymethyl)-1-(2H-tetrazol-5-ylmethyl)benzimidazol-4-yl]oxymethyl]cyclohexan-1-ol	IC50	55000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
3-[[5,6-dichloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]cyclohexan-1-ol	IC50	55000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
[4-[[(1S,2R)-2-aminocyclohexyl]methoxy]-5,6-dichloro-1H-benzimidazol-2-yl]methanol	IC50	200000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
2-[[6-chloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]cyclohexan-1-ol	IC50	200000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
[5,6-dichloro-4-(oxolan-2-ylmethoxy)-1H-benzimidazol-2-yl]methanol	IC50	200000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
6-[[5,6-dichloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]piperidin-2-one	IC50	200000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
4-bromo-6-(3,4-dichlorophenyl)sulfanyl-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-1H-indole-2-carboxamide	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
4-bromo-6-(3,4-dichlorophenyl)sulfanyl-N-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-1H-indole-2-carboxamide	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
1-[6-chloro-4-(4-chlorophenyl)sulfanyl-1H-indole-2-carbonyl]piperidine-3-carboxamide	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
N-[(1-benzylpyrrolidin-3-yl)methyl]-6-chloro-4-(4-chlorophenyl)sulfanyl-1H-indole-2-carboxamide	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
6-chloro-4-(4-chlorophenyl)sulfanyl-N-[(5-oxopyrrolidin-2-yl)methyl]-1H-indole-2-carboxamide	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
(6-phenoxy-4-piperidin-3-yl-1H-indol-2-yl)methanol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
[6-(benzenesulfinyl)-4-bromo-1H-indol-2-yl]methanol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
4-(2-chlorophenyl)sulfinyl-1H-indole	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
4-(3-chlorophenyl)sulfinyl-1H-indole	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
4-(5,6-dichloro-1H-benzimidazol-2-yl)-N-[[(2S)-1-methylpyrrolidin-2-yl]methyl]benzamide	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
4-(5,6-dichloro-1H-benzimidazol-2-yl)-N-[[(2R)-1-methylpyrrolidin-2-yl]methyl]benzamide	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
2-[[5,6-dichloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]cyclopentan-1-ol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
4-[[5,6-dichloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]oxolan-3-ol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
(3R,4S)-3-[[5,6-dichloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]piperidin-4-ol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
(3R,4R)-3-[[5,6-dichloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]piperidin-4-ol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
trans-(1R,2R)-2-[[5,6-dichloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]cyclohexan-1-ol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
cis-(1S,2R)-2-[[5,6-dichloro-2-(hydroxymethyl)-1-(1H-1,2,4-triazol-5-ylmethyl)benzimidazol-4-yl]oxymethyl]cyclohexan-1-ol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
[5,6-dichloro-4-(oxan-2-ylmethoxy)-1H-benzimidazol-2-yl]methanol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
5-[[5,6-dichloro-2-(hydroxymethyl)-1H-benzimidazol-4-yl]oxymethyl]pyrrolidin-2-one	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
[5,6-dichloro-4-(pyrrolidin-3-ylmethoxy)-1H-benzimidazol-2-yl]methanol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
[5,6-dichloro-4-(piperidin-2-ylmethoxy)-1H-benzimidazol-2-yl]methanol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof
[5,6-dichloro-4-(pyrrolidin-2-ylmethoxy)-1H-benzimidazol-2-yl]methanol	IC50	550000 nM	US-11339144: Heteroaryl Rheb inhibitors and uses thereof

CTD chemical–gene interactions

61 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects expression, decreases expression	4
sodium arsenite	decreases expression, increases abundance, increases expression	4
Tobacco Smoke Pollution	affects expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
Benzo(a)pyrene	affects methylation	2
Cadmium	decreases expression, increases abundance, increases expression	2
Zinc	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
bisphenol F	increases expression	1
moringin	affects cotreatment, increases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression, increases expression	1
tetrabromobisphenol A	decreases expression	1
ochratoxin A	affects binding	1
benzo(e)pyrene	increases methylation	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
ochratoxin B	affects binding	1
chloropicrin	affects expression	1
lonafarnib	decreases activity, increases response to substance	1
tipifarnib	decreases activity, increases response to substance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3112177	Binding	Inhibition of RHEB in human HeLa cells assessed as decrease in phospho-S6 protein level at 100 uM after 4 hrs by Western blotting analysis	Bisphenol A binds to Ras proteins and competes with guanine nucleotide exchange: implications for GTPase-selective antagonists. — J Med Chem

Clinical trials (associated diseases)

267 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome