EIF4A3

Summary

EIF4A3 (eukaryotic translation initiation factor 4A3, HGNC:18683) is a protein-coding gene on chromosome 17q25.3, encoding Eukaryotic initiation factor 4A-III (P38919). ATP-dependent RNA helicase. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

This gene encodes a member of the DEAD box protein family. DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The protein encoded by this gene is a nuclear matrix protein. Its amino acid sequence is highly similar to the amino acid sequences of the translation initiation factors eIF4AI and eIF4AII, two other members of the DEAD box protein family.

Source: NCBI Gene 9775 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Richieri Costa-Pereira syndrome (Definitive, GenCC)
• GWAS associations: 17
• Clinical variants (ClinVar): 56 total — 4 pathogenic
• Phenotypes (HPO): 55
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_014740

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18683
Approved symbol	EIF4A3
Name	eukaryotic translation initiation factor 4A3
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0111, EIF4AIII, Fal1
Ensembl gene	ENSG00000141543
Ensembl biotype	protein_coding
OMIM	608546
Entrez	9775

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 6 retained_intron

ENST00000570625, ENST00000570837, ENST00000575668, ENST00000575957, ENST00000575978, ENST00000576547, ENST00000576573, ENST00000647795, ENST00000649764, ENST00000863000, ENST00000863001, ENST00000938285, ENST00000938286, ENST00000943420

RefSeq mRNA: 2 — MANE Select: NM_014740 NM_001411099, NM_014740

CCDS: CCDS11767, CCDS92411

Canonical transcript exons

ENST00000649764 — 12 exons

Exon	Start	End
ENSE00000949586	80141782	80141848
ENSE00000949587	80141319	80141381
ENSE00000949589	80139670	80139750
ENSE00000949591	80139021	80139162
ENSE00001303885	80140008	80140140
ENSE00003301857	80137386	80137501
ENSE00003359532	80138142	80138280
ENSE00003467898	80136228	80136335
ENSE00003478556	80144172	80144244
ENSE00003676876	80136004	80136131
ENSE00003837591	80146793	80147128
ENSE00003837667	80134369	80135506

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 47.0479 / max 936.4674, expressed in 1824 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168606	19.7611	1808
168604	14.8341	1798
168605	9.5663	1725
168603	1.9092	1112
168602	0.9772	638

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	98.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.14	gold quality
endometrium epithelium	UBERON:0004811	97.67	gold quality
left uterine tube	UBERON:0001303	97.57	gold quality
pharyngeal mucosa	UBERON:0000355	97.52	gold quality
olfactory bulb	UBERON:0002264	97.26	gold quality
ventricular zone	UBERON:0003053	97.21	gold quality
esophagus mucosa	UBERON:0002469	97.17	gold quality
mucosa of urinary bladder	UBERON:0001259	97.05	gold quality
gingival epithelium	UBERON:0001949	97.04	gold quality
left ovary	UBERON:0002119	97.03	gold quality
right ovary	UBERON:0002118	96.97	gold quality
gingiva	UBERON:0001828	96.88	gold quality
skin of abdomen	UBERON:0001416	96.83	gold quality
ovary	UBERON:0000992	96.74	gold quality
penis	UBERON:0000989	96.71	gold quality
skin of leg	UBERON:0001511	96.50	gold quality
esophagus squamous epithelium	UBERON:0006920	96.41	gold quality
islet of Langerhans	UBERON:0000006	96.40	gold quality
ectocervix	UBERON:0012249	96.39	gold quality
left adrenal gland	UBERON:0001234	96.28	gold quality
epithelium of esophagus	UBERON:0001976	96.19	gold quality
left adrenal gland cortex	UBERON:0035825	96.19	gold quality
mucosa of transverse colon	UBERON:0004991	96.18	gold quality
peritoneum	UBERON:0002358	96.12	gold quality
zone of skin	UBERON:0000014	96.11	gold quality
cartilage tissue	UBERON:0002418	96.11	gold quality
omental fat pad	UBERON:0010414	96.11	gold quality
right adrenal gland	UBERON:0001233	96.08	gold quality
adrenal gland	UBERON:0002369	96.08	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	42.71
E-CURD-97	no	823.58
E-GEOD-81383	no	789.91
E-MTAB-10137	no	5.45
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

24 targeting EIF4A3, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-6507-3P	99.35	67.32	1059
HSA-MIR-1253	99.12	67.08	1688
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-6871-5P	98.90	66.67	671
HSA-MIR-9903	98.47	66.70	748
HSA-MIR-6771-3P	98.20	66.53	971
HSA-MIR-4433A-3P	97.75	62.82	1435
HSA-MIR-3665	97.73	65.08	975

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• NMP 265, a common part of the nuclear matrix, is located in the nucleus via an N-terminal amino acid sequence. (PMID:10623621)
• identification of eIF4AIII and Barentsz as components of a conserved protein complex that is essential for mRNA localization in flies and nonsense-mediated mRNA decay in mammals (PMID:14973490)
• eIF4AIII represents a new functional class of DExH/D box proteins that act as RNA clamps or ‘place holders’ for the sequence-independent attachment of additional factors to RNAs. (PMID:15034551)
• detection of autoantibodies to DDX48 may have clinical utility for the improved diagnosis of pancreatic cancer (PMID:15796914)
• The stable association of multiprotein exon junction complex core with RNA is maintained by inhibition of eIF4AIII ATPase activity by MAGOH-Y14. (PMID:16170325)
• crystal structure of a tetrameric exon junction core complex containing the DEAD-box adenosine triphosphatase eukaryotic initiation factor 4AIII bound to an ATP analog, MAGOH, Y14, a fragment of MLN51, and a polyuracil mRNA mimic (PMID:16931718)
• Although it is dispensable for pre-mRNA splicing in vitro, eIF4A3 is required for splicing-dependent loading of the Y14-Magoh core heterodimer onto mRNA. (PMID:17606899)
• Data show that eIF4AIII, a core exon junction complex (EJC) component loaded onto mRNAs by pre-mRNA splicing, is associated with neuronal mRNA granules and dendritic mRNAs. (PMID:17632064)
• The nonsense-mediated-decay mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers. (PMID:18427545)
• demonstrate direct physical interactions between yeast Sgd1p and Fal1p, and between their human orthologs (NOM1 and eIF4AIII) in vitro and in vivo, identifying human NOM1 as a missing eIF4G-like interacting partner of eIF4AIII (PMID:21576267)
• CWC22 escorts the helicase eIF4AIII to spliceosomes and promotes exon junction complex assembly (PMID:22961380)
• The binding mode of CWC22 to eIF4AIII reveals a facet of how MIF4G domains use their versatile structural frameworks to activate or inhibit DEAD-box proteins. (PMID:24218557)
• EIF4A3 is a gene involved in RNA metabolism, plays a role in mandible, laryngeal, and limb morphogenesis. Richieri-Costa-Pereira syndrome is caused by mutations in EIF4A3. (PMID:24360810)
• Host eIF4AIII RNA helicase is required for efficient human cytomegalovirus replication. (PMID:26773380)
• High EIF4A expression is associated with malignant peripheral nerve sheath tumors and vestibular schwannomas. (PMID:26951381)
• we firstly report that the lncRNA H19 recruits eIF4A3 and promotes the colorectal cancer cell proliferation (PMID:26989025)
• MYC, DUX4, and EIF4A3 might contribute to facioscapulohumeral dystrophy pathophysiology (PMID:28273136)
• Although the most frequent mutation in this study was the recurrent 16-repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation. (PMID:29112243)
• FAL1 may work as a ceRNA to modulate AKT1 expression via competitively binding to miR-637 in HSCR. (PMID:30062828)
• EIF4A3-induced circMMP9 is an important underlying mechanism in GBM cell proliferation. (PMID:30470262)
• eIF4A3 is phosphorylated at threonine 163 by CDK1 and CDK2. T163 phosphorylation affects nonsense-mediated mRNA decay efficiency in a cell cycle-dependent manner. (PMID:30784594)
• Pharmacological systems analysis defines EIF4A3 functions in cell-cycle and RNA stress granule formation. (PMID:31069274)
• We demonstrate that eIF4A3 stimulates Alyref deposition not only on spliced RNAs close to exon junction complex sites but also on single-exon transcripts (PMID:31104896)
• Comprehensive analysis of biological networks and the eukaryotic initiation factor 4A-3 gene as pivotal in hepatocellular carcinoma. (PMID:31898336)
• Eukaryotic initiation Factor 4AIII facilitates hepatocellular carcinoma cell proliferation, migration, and epithelial-mesenchymal transition process via antagonistically binding to WD repeat domain 66 with miRNA-2113. (PMID:31975383)
• The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer. (PMID:32264877)
• LINC00667 promotes the proliferation, migration, and pathological angiogenesis in non-small cell lung cancer through stabilizing VEGFA by EIF4A3. (PMID:32281700)
• lncRNA HOXC-AS1 promotes gastric cancer via binding eIF4AIII by activating Wnt/beta-catenin signaling. (PMID:32307743)
• CRISPR-Based Screen Links an Inhibitor of Nonsense-Mediated Decay to eIF4A3 Target Engagement. (PMID:32401488)
• Circ_cse1l Inhibits Colorectal Cancer Proliferation by Binding to eIF4A3. (PMID:32857753)
• The exon junction complex core factor eIF4A3 is a key regulator of HPV16 gene expression. (PMID:33760064)
• Hsa_circ_0030042 regulates abnormal autophagy and protects atherosclerotic plaque stability by targeting eIF4A3. (PMID:33859754)
• EIF4A3-induced circ_0084615 contributes to the progression of colorectal cancer via miR-599/ONECUT2 pathway. (PMID:34253241)
• hsa_circ_0101119 facilitates the progression of cervical cancer via an interaction with EIF4A3 to inhibit TCEAL6 expression. (PMID:34278492)
• EIF4A3: a gatekeeper of autophagy. (PMID:34643458)
• circ-SIRT1 Promotes Colorectal Cancer Proliferation and EMT by Recruiting and Binding to eIF4A3. (PMID:34660182)
• Hsa_circ_0004296 inhibits metastasis of prostate cancer by interacting with EIF4A3 to prevent nuclear export of ETS1 mRNA. (PMID:34696782)
• YY1 and eIF4A3 are mediators of the cell proliferation, migration and invasion in cholangiocarcinoma promoted by circ-ZNF609 by targeting miR-432-5p to regulate LRRC1. (PMID:34898474)
• eIF4A3-induced circWAC promotes breast cancer progression through mediating miR-599/E2F3 axis. (PMID:34989110)
• EIF4A3-induced circCCNB1 (hsa_circ_0001495) promotes glioma progression by elevating CCND1 through interacting miR-516b-5p and HuR. (PMID:35038081)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif4a3	ENSDARG00000102978
mus_musculus	Eif4a3	ENSMUSG00000025580
mus_musculus	Eif4a3l1	ENSMUSG00000094973
mus_musculus	Eif4a3l2	ENSMUSG00000107906
rattus_norvegicus	Eif4a3	ENSRNOG00000045791
drosophila_melanogaster	CG7483	FBGN0037573
caenorhabditis_elegans	F33D11.10	WBGENE00018007
caenorhabditis_elegans	eif-4A3	WBGENE00022029

Paralogs (38): DDX20 (ENSG00000064703), DDX3Y (ENSG00000067048), DDX1 (ENSG00000079785), DDX43 (ENSG00000080007), DDX18 (ENSG00000088205), DDX24 (ENSG00000089737), DDX17 (ENSG00000100201), DDX49 (ENSG00000105671), DDX50 (ENSG00000107625), DDX5 (ENSG00000108654), DDX25 (ENSG00000109832), DDX6 (ENSG00000110367), DDX55 (ENSG00000111364), DDX59 (ENSG00000118197), DDX54 (ENSG00000123064), DDX39A (ENSG00000123136), DDX27 (ENSG00000124228), DDX31 (ENSG00000125485), DDX56 (ENSG00000136271), DDX46 (ENSG00000145833), DDX4 (ENSG00000152670), EIF4A2 (ENSG00000156976), DDX19B (ENSG00000157349), EIF4A1 (ENSG00000161960), DDX21 (ENSG00000165732), DDX19A (ENSG00000168872), TDRD12 (ENSG00000173809), DDX23 (ENSG00000174243), DDX10 (ENSG00000178105), DDX28 (ENSG00000182810), DDX41 (ENSG00000183258), DDX53 (ENSG00000184735), DDX51 (ENSG00000185163), DDX42 (ENSG00000198231), DDX39B (ENSG00000198563), DDX47 (ENSG00000213782), DDX3X (ENSG00000215301), DDX52 (ENSG00000278053)

Protein

Protein identifiers

Eukaryotic initiation factor 4A-III — P38919 (reviewed: P38919)

Alternative names: ATP-dependent RNA helicase DDX48, ATP-dependent RNA helicase eIF4A-3, DEAD box protein 48, Eukaryotic initiation factor 4A-like NUK-34, Eukaryotic translation initiation factor 4A isoform 3, Nuclear matrix protein 265

All UniProt accessions (2): P38919, I3L3H2

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent RNA helicase. Involved in pre-mRNA splicing as component of the spliceosome. Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). Its RNA-dependent ATPase and RNA-helicase activities are induced by CASC3, but abolished in presence of the MAGOH-RBM8A heterodimer, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The inhibition of ATPase activity by the MAGOH-RBM8A heterodimer increases the RNA-binding affinity of the EJC. Involved in translational enhancement of spliced mRNAs after formation of the 80S ribosome complex. Binds spliced mRNA in sequence-independent manner, 20-24 nucleotides upstream of mRNA exon-exon junctions. Shows higher affinity for single-stranded RNA in an ATP-bound core EJC complex than after the ATP is hydrolyzed. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly. Involved in craniofacial development.

Subunit / interactions. Identified in the spliceosome C complex. Core component of the mRNA splicing-dependent exon junction complex (EJC); the core complex contains CASC3, EIF4A3, MAGOH or MAGOHB, and RBM8A. Interacts with CASC3, MAGOH, NXF1, RBM8A and ALYREF/THOC4. Component of the ALYREF/THOC4-EJC-RNA complex; in the complex interacts with MAGOH, RBM8A and THOC4 (via the WXHD motif); these interactions are likely specific to RNA-bound EJC. May interact with NOM1. Interacts with POLDIP3. Interacts with CWC22 and PRPF19 in an RNA-independent manner. Direct interaction with CWC22 is mediated by the helicase C-terminal domain. Full interaction with CWC22 occurs only when EIF4A3 is not part of the EJC and prevents EIF4A3 binding to RNA. Identified in a complex composed of the EJC core, UPF3B and UPF2. The EJC core can also interact with UPF3A (in vitro). Interacts with NCBP3. Interacts with NRDE2. Interacts with DHX34; the interaction is RNA-independent.

Subcellular location. Nucleus. Nucleus speckle. Cytoplasm.

Tissue specificity. Ubiquitously expressed.

Disease relevance. Richieri-Costa-Pereira syndrome (RCPS) [MIM:268305] A syndrome characterized by a unique pattern of anomalies consisting of microstomia, micrognathia, abnormal fusion of mandible, cleft palate/Robin sequence, absence of central lower incisors, minor ears anomalies, hypoplastic first ray, abnormal tibiae, hypoplastic halluces, and clubfeet. Learning disability is also a common finding. The disease is caused by variants affecting the gene represented in this entry. EIF4A3 mutations resulting in Richieri-Costa-Pereira syndrome include a repeat expansion of 18 or 20 nucleotides in the 5’ untranslated region. Affected individuals have 14 to 16 repeats, while healthy individuals have 3 to 12 repeats.

Activity regulation. The ATPase activity is increased some 4-fold in the presence of RNA.

Similarity. Belongs to the DEAD box helicase family. eIF4A subfamily.

RefSeq proteins (2): NP_001398028, NP_055555* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000629	RNA-helicase_DEAD-box_CS	Conserved_site
IPR001650	Helicase_C-like	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR014014	RNA_helicase_DEAD_Q_motif	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00270, PF00271

Enzyme classification (BRENDA):

• EC 3.6.4.13 — RNA helicase (BRENDA: 3 organisms, 3 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (84 total): helix 23, strand 21, mutagenesis site 10, modified residue 9, binding site 5, cross-link 5, chain 2, domain 2, sequence conflict 2, short sequence motif 2, initiator methionine 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
4C9B	X-RAY DIFFRACTION	2
2J0S	X-RAY DIFFRACTION	2.21
2HYI	X-RAY DIFFRACTION	2.3
3EX7	X-RAY DIFFRACTION	2.3
7ZNJ	ELECTRON MICROSCOPY	2.4
8C6J	ELECTRON MICROSCOPY	2.8
2J0U	X-RAY DIFFRACTION	3
6ICZ	ELECTRON MICROSCOPY	3
6YVH	X-RAY DIFFRACTION	3.19
2J0Q	X-RAY DIFFRACTION	3.2
2HXY	X-RAY DIFFRACTION	3.3
6QDV	ELECTRON MICROSCOPY	3.3
9FMD	ELECTRON MICROSCOPY	3.3
2XB2	X-RAY DIFFRACTION	3.4
8I0W	ELECTRON MICROSCOPY	3.4
5XJC	ELECTRON MICROSCOPY	3.6
7W59	ELECTRON MICROSCOPY	3.6
7W5A	ELECTRON MICROSCOPY	3.6
5YZG	ELECTRON MICROSCOPY	4.1
7W5B	ELECTRON MICROSCOPY	4.3
7A5P	ELECTRON MICROSCOPY	5
5MQF	ELECTRON MICROSCOPY	5.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P38919-F1	88.93	0.68

Functional residue map

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

Ligand- & substrate-binding residues (5): 342; 367–371; 60; 65; 85–90

Post-translational modifications (14): 1, 2, 10, 12, 124, 163, 198, 296, 321, 19, 152, 314, 374, 382

Mutagenesis-validated functional residues (10):

Position	Phenotype
88	atpase activity is not increased by the presence of casc3. does not prevent ejc formation. prevents the ejc disassembly.
99	no effect on interaction with cwc22.
270	loss of cwc22-binding and loss of incorporation into ejcs; when associated with k-273.
273	loss of cwc22-binding and loss of incorporation into ejcs; when associated with k-270.
276–277	loss of cwc22-binding and loss of incorporation into ejcs.
300–301	decreased interaction with cwc22.
301–303	loss of cwc22-binding and loss of incorporation into ejcs.
334	reduced incorporation into ejcs.
401	loss of incorporation into ejcs; when associated with r-402.
402	loss of incorporation into ejcs; when associated with k-401.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-159236	Transport of Mature mRNA derived from an Intron-Containing Transcript
R-HSA-429947	Deadenylation of mRNA
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-72187	mRNA 3’-end processing
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-975957	Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)
R-HSA-9820841	M-decay: degradation of maternal mRNAs by maternally stored factors
R-HSA-9820865	Z-decay: degradation of maternal mRNAs by zygotically expressed factors
R-HSA-9918481	Dengue Virus-Host Interactions
R-HSA-9918487	Dengue Virus Genome Translation and Replication
R-HSA-73856	RNA Polymerase II Transcription Termination

MSigDB gene sets: 421 (showing top): GOBP_RIBOSOME_BIOGENESIS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_ASSOCIATIVE_LEARNING, GOBP_EMBRYONIC_SKELETAL_SYSTEM_MORPHOGENESIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HSIAO_HOUSEKEEPING_GENES, GOBP_REGULATION_OF_TRANSLATIONAL_ELONGATION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION

GO Biological Process (20): nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184), mRNA splicing, via spliceosome (GO:0000398), rRNA processing (GO:0006364), mRNA export from nucleus (GO:0006406), associative learning (GO:0008306), negative regulation of translation (GO:0017148), exploration behavior (GO:0035640), positive regulation of translation (GO:0045727), embryonic cranial skeleton morphogenesis (GO:0048701), cellular response to selenite ion (GO:0072715), negative regulation of excitatory postsynaptic potential (GO:0090394), regulation of translation at postsynapse, modulating synaptic transmission (GO:0099578), negative regulation of selenocysteine incorporation (GO:1904570), cellular response to brain-derived neurotrophic factor stimulus (GO:1990416), regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:2000622), mRNA processing (GO:0006397), regulation of translation (GO:0006417), RNA splicing (GO:0008380), negative regulation of gene expression (GO:0010629), mRNA transport (GO:0051028)

GO Molecular Function (14): RNA binding (GO:0003723), RNA helicase activity (GO:0003724), mRNA binding (GO:0003729), ATP binding (GO:0005524), poly(A) binding (GO:0008143), ATP hydrolysis activity (GO:0016887), selenocysteine insertion sequence binding (GO:0035368), RNA stem-loop binding (GO:0035613), ribonucleoprotein complex binding (GO:0043021), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (16): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear speck (GO:0016607), dendrite (GO:0030425), exon-exon junction complex (GO:0035145), neuronal cell body (GO:0043025), U2-type catalytic step 1 spliceosome (GO:0071006), catalytic step 2 spliceosome (GO:0071013), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), spliceosomal complex (GO:0005681), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Maternal to zygotic transition (MZT)	2
Dengue Virus Infection	2
Antimicrobial mechanism of IFN-stimulated genes	1
Transport of Mature Transcript to Cytoplasm	1
Deadenylation-dependent mRNA decay	1
mRNA Splicing	1
Processing of Capped Intron-Containing Pre-mRNA	1
Signaling by ROBO receptors	1
Nonsense-Mediated Decay (NMD)	1
RNA Polymerase II Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
translation	4
RNA processing	3
gene expression	2
regulation of translation	2
RNA binding	2
ATP-dependent activity	2
binding	2
nuclear lumen	2
nuclear protein-containing complex	2
synapse	2
nuclear-transcribed mRNA catabolic process	1
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
rRNA metabolic process	1
ribosome biogenesis	1
RNA export from nucleus	1
mRNA transport	1
learning	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
behavior	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
embryonic skeletal system morphogenesis	1
cranial skeletal system development	1
response to selenite ion	1
cellular response to oxygen-containing compound	1
negative regulation of biological process	1
excitatory postsynaptic potential	1
modulation of excitatory postsynaptic potential	1
chemical synaptic transmission	1
postsynapse	1
postsynaptic modulation of chemical synaptic transmission	1
regulation of translation at synapse, modulating synaptic transmission	1
regulation of translation at postsynapse	1
selenocysteine incorporation	1
negative regulation of translational elongation	1
regulation of selenocysteine incorporation	1
cellular response to nerve growth factor stimulus	1

Protein interactions and networks

STRING

5092 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF4A3	CASC3	O15234	999
EIF4A3	MAGOHB	Q96A72	999
EIF4A3	MAGOH	P50606	999
EIF4A3	RBM8A	Q9Y5S9	997
EIF4A3	UPF3B	Q9BZI7	991
EIF4A3	EIF4E	P06730	984
EIF4A3	CWC22	Q9HCG8	974
EIF4A3	EIF4G1	Q04637	974
EIF4A3	ALYREF	Q86V81	966
EIF4A3	RNPS1	Q15287	954
EIF4A3	UPF3A	Q9H1J1	951
EIF4A3	UPF1	Q92900	947
EIF4A3	UPF2	Q9HAU5	892
EIF4A3	EIF4A1	P04765	890
EIF4A3	EIF4A2	Q14240	853

IntAct

379 interactions, top by confidence:

A	B	Type	Score
CASC3	EIF4A3	psi-mi:“MI:0915”(physical association)	0.980
CASC3	EIF4A3	psi-mi:“MI:0914”(association)	0.980
EIF4A3	CASC3	psi-mi:“MI:0915”(physical association)	0.980
EIF4A3	CASC3	psi-mi:“MI:0407”(direct interaction)	0.980
EIF4A3	CASC3	psi-mi:“MI:0914”(association)	0.980
MAGOH	CASC3	psi-mi:“MI:0914”(association)	0.970

BioGRID (731): EIF4A3 (Affinity Capture-Western), EIF4A3 (Affinity Capture-MS), PDCD4 (Two-hybrid), CDCA7L (Two-hybrid), EIF4A3 (Affinity Capture-MS), EIF4A3 (Affinity Capture-MS), EIF4A3 (Affinity Capture-MS), EIF4A3 (Affinity Capture-MS), EIF4A3 (Affinity Capture-MS), EIF4A3 (Affinity Capture-MS), EIF4A3 (Affinity Capture-MS), EIF4A3 (Affinity Capture-MS), EIF4A3 (Reconstituted Complex), EIF4A3 (Affinity Capture-MS), EIF4A3 (Affinity Capture-MS)

ESM2 similar proteins: A1C595, A1D071, A2QEN5, A4QU31, A4QVP2, A5A6N4, A5AAE5, A6M931, A6R3R5, A6RJ45, A6S4N4, A7EGL7, A7EM88, B5DG42, B5FZY7, B7ZTW1, P0CQ72, P0CQ73, P38919, P47943, P60842, P60843, Q02748, Q0CAS8, Q0UU86, Q10055, Q10I26, Q1DQ20, Q1DTB3, Q2GWJ5, Q2HFP1, Q2NL22, Q2UAK1, Q3B8Q2, Q3SZ54, Q4IAA0, Q4P184, Q4R3Q1, Q4R8K5, Q4WEB4

Diamond homologs: A0A1D5PRR9, A1CS00, A1D4V5, A2Q8R2, A3GH78, A3LP87, A4RGD1, A4RN08, A5AA68, A5DKW3, A5E0U9, A6M931, A6RIS1, A6SFV4, A6ZVS0, A7A0P8, A7E436, A7EFH4, A7TSV4, B0XMV6, B5DG42, B5FZY7, B7ZTW1, E7F8F4, I3XHK1, O42226, P0C2N8, P0CQ98, P0CQ99, P0CR00, P0CR01, P0CR02, P0CR03, P32892, P34689, P37954, P38919, P40562, P42305, P84634

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
EIF4A3	“form complex”	“Exon junction complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 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
Transport of Mature Transcript to Cytoplasm	8	37.6×	3e-09
mRNA 3’-end processing	12	29.2×	2e-12
Transport of Mature mRNA derived from an Intron-Containing Transcript	12	22.6×	3e-11
RNA Polymerase II Transcription Termination	8	21.7×	3e-07
Processing of Capped Intron-Containing Pre-mRNA	13	13.2×	2e-09
mRNA Splicing	8	10.8×	4e-05
Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)	7	8.4×	1e-03
mRNA Splicing - Major Pathway	12	8.1×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
mRNA export from nucleus	12	34.1×	7e-13
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	5	22.5×	5e-04
RNA splicing	11	9.3×	1e-05
mRNA splicing, via spliceosome	9	7.9×	5e-04
mRNA processing	9	6.8×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	26
Likely benign	9
Benign	4

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
101500	NM_014740.4(EIF4A3):c.-98_-81delinsTCGGCAGCGGCACAGCGAGG[13]	Pathogenic
101501	NG_046916.1:g.5125_5142delinsTCGGCAGCGGCACAGCGAGG[12]	Pathogenic
101502	NM_014740.4(EIF4A3):c.-98_-81del18insTCGGCAGCGGCACAGCGAGG[10]	Pathogenic
101503	NM_014740.4(EIF4A3):c.809A>G (p.Asp270Gly)	Pathogenic

SpliceAI

1034 predictions. Top by Δscore:

Variant	Effect	Δscore
17:80135502:AGCAA:A	acceptor_gain	1.0000
17:80135503:GCAA:G	acceptor_gain	1.0000
17:80135504:CAA:C	acceptor_gain	1.0000
17:80135504:CAAC:C	acceptor_gain	1.0000
17:80135505:AA:A	acceptor_gain	1.0000
17:80135507:C:CC	acceptor_gain	1.0000
17:80135999:CCTA:C	donor_loss	1.0000
17:80136001:TA:T	donor_loss	1.0000
17:80136002:A:AC	donor_gain	1.0000
17:80136002:AC:A	donor_loss	1.0000
17:80136003:C:CC	donor_gain	1.0000
17:80136003:CCG:C	donor_loss	1.0000
17:80136003:CCGTT:C	donor_gain	1.0000
17:80136127:CAATT:C	acceptor_gain	1.0000
17:80136128:AATT:A	acceptor_gain	1.0000
17:80136129:ATT:A	acceptor_gain	1.0000
17:80136129:ATTC:A	acceptor_loss	1.0000
17:80136130:TT:T	acceptor_gain	1.0000
17:80136132:C:CA	acceptor_loss	1.0000
17:80136132:C:CC	acceptor_gain	1.0000
17:80136135:C:CT	acceptor_gain	1.0000
17:80136136:A:T	acceptor_gain	1.0000
17:80136140:A:AC	acceptor_gain	1.0000
17:80136331:CTCGG:C	acceptor_gain	1.0000
17:80137381:CCCA:C	donor_loss	1.0000
17:80137382:CCA:C	donor_loss	1.0000
17:80137384:A:C	donor_loss	1.0000
17:80137385:C:CA	donor_loss	1.0000
17:80137500:ACCT:A	acceptor_loss	1.0000
17:80137501:CCT:C	acceptor_loss	1.0000

AlphaMissense

2710 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:80136086:G:C	N379K	1.000
17:80136086:G:T	N379K	1.000
17:80136099:C:T	G375D	1.000
17:80136100:C:G	G375R	1.000
17:80136117:C:T	G369D	1.000
17:80136126:C:T	G366E	1.000
17:80136127:C:A	G366W	1.000
17:80136127:C:G	G366R	1.000
17:80136127:C:T	G366R	1.000
17:80136131:T:A	R364S	1.000
17:80136131:T:G	R364S	1.000
17:80136228:C:A	R364I	1.000
17:80136228:C:G	R364T	1.000
17:80136266:G:C	N351K	1.000
17:80136266:G:T	N351K	1.000
17:80136276:A:G	L348P	1.000
17:80136301:C:G	G340R	1.000
17:80136301:C:T	G340R	1.000
17:80136318:G:A	T334I	1.000
17:80136327:A:G	L331P	1.000
17:80137491:A:G	L293P	1.000
17:80138157:G:C	C284W	1.000
17:80138158:C:T	C284Y	1.000
17:80138160:G:C	F283L	1.000
17:80138160:G:T	F283L	1.000
17:80138162:A:G	F283L	1.000
17:80138171:C:G	A280P	1.000
17:80138197:A:G	L271P	1.000
17:80138206:A:G	L268P	1.000
17:80138247:A:C	F254L	1.000

dbSNP variants (sampled 300 via entrez): RS1000173409 (17:80145708 T>C), RS1000379031 (17:80134576 C>T), RS1000786144 (17:80148291 C>G,T), RS1000823935 (17:80136137 G>A,C), RS1000922139 (17:80148472 G>C), RS1001105736 (17:80146976 G>A), RS1001461384 (17:80141788 A>C,G), RS1001530036 (17:80144445 T>C), RS1001555610 (17:80140750 T>C), RS1001562706 (17:80146189 G>A), RS1001879209 (17:80133884 A>G), RS1002195448 (17:80144540 T>C), RS1002246441 (17:80144893 C>A,T), RS1002289440 (17:80142099 T>C), RS1002363270 (17:80136219 G>A,C)

Disease associations

OMIM: gene MIM:608546 | disease phenotypes: MIM:268305

GenCC curated gene-disease

Disease	Classification	Inheritance
Richieri Costa-Pereira syndrome	Definitive	Autosomal recessive

Mondo (1): Richieri Costa-Pereira syndrome (MONDO:0009998)

Orphanet (1): Richieri Costa-Pereira syndrome (Orphanet:3102)

HPO phenotypes

55 total (30 of 55 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000201	Pierre-Robin sequence
HP:0000218	High palate
HP:0000308	Microretrognathia
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000411	Protruding ear
HP:0000448	Prominent nose
HP:0000690	Agenesis of maxillary lateral incisor
HP:0000750	Delayed speech and language development
HP:0001245	Small thenar eminence
HP:0001263	Global developmental delay
HP:0001328	Specific learning disability
HP:0001608	Abnormality of the voice
HP:0001609	Hoarse voice
HP:0001762	Talipes equinovarus
HP:0002643	Neonatal respiratory distress
HP:0002827	Hip dislocation
HP:0002984	Hypoplasia of the radius
HP:0003038	Fibular hypoplasia
HP:0003577	Congenital onset
HP:0004209	Clinodactyly of the 5th finger
HP:0004322	Short stature
HP:0004987	Mesomelic leg shortening
HP:0005011	Mesomelic arm shortening
HP:0005736	Short tibia

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST003471_8	Myocardial infarction	2.000000e-07
GCST004611_136	High light scatter reticulocyte count	3.000000e-21
GCST004612_85	High light scatter reticulocyte percentage of red cells	2.000000e-22
GCST004619_135	Reticulocyte fraction of red cells	1.000000e-18
GCST004622_62	Reticulocyte count	3.000000e-16
GCST004628_26	Immature fraction of reticulocytes	2.000000e-15
GCST90002385_330	High light scatter reticulocyte count	1.000000e-15
GCST90002385_331	High light scatter reticulocyte count	2.000000e-44
GCST90002386_79	High light scatter reticulocyte percentage of red cells	2.000000e-16
GCST90002386_80	High light scatter reticulocyte percentage of red cells	6.000000e-46
GCST90002387_207	Immature fraction of reticulocytes	2.000000e-33
GCST90002396_679	Mean reticulocyte volume	1.000000e-25
GCST90002397_376	Mean spheric corpuscular volume	1.000000e-20
GCST90002405_558	Reticulocyte count	4.000000e-14
GCST90002405_559	Reticulocyte count	8.000000e-36
GCST90002406_505	Reticulocyte fraction of red cells	3.000000e-15
GCST90002406_506	Reticulocyte fraction of red cells	2.000000e-38

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535677	Richieri Costa Pereira syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105832 (SINGLE PROTEIN)

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

ChEMBL bioactivities

51 potent at pChembl≥5 of 63 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.37	Kd	43	nM	CHEMBL4073833
7.30	IC50	50	nM	CHEMBL4162764
7.24	Kd	57	nM	CHEMBL4070071
7.21	Kd	62	nM	CHEMBL4070102
7.13	Kd	73.93	nM	CHEMBL5653589
7.13	ED50	73.93	nM	CHEMBL5653589
7.00	IC50	100	nM	CHEMBL4170030
6.96	IC50	110	nM	CHEMBL4070071
6.85	IC50	140	nM	CHEMBL4175313
6.72	IC50	190	nM	CHEMBL4176393
6.70	Kd	200	nM	CHEMBL4070102
6.70	IC50	200	nM	CHEMBL4070071
6.58	IC50	260	nM	CHEMBL4073833
6.55	IC50	280	nM	CHEMBL4168783
6.54	IC50	290	nM	CHEMBL4173010
6.54	IC50	290	nM	CHEMBL4172770
6.44	IC50	360	nM	CHEMBL4070102
6.44	IC50	360	nM	CHEMBL4104965
6.41	IC50	390	nM	CHEMBL4080736
6.39	IC50	410	nM	CHEMBL4169616
6.38	IC50	420	nM	CHEMBL4061398
6.38	IC50	420	nM	CHEMBL4164548
6.37	Ki	430	nM	CHEMBL4070102
6.31	IC50	490	nM	CHEMBL4176581
6.24	IC50	580	nM	CHEMBL4097260
6.22	IC50	600	nM	CHEMBL4087208
6.18	IC50	660	nM	CHEMBL4070582
6.16	IC50	700	nM	CHEMBL4168400
6.14	IC50	720	nM	CHEMBL4092418
6.12	IC50	750	nM	CHEMBL4159400
6.08	IC50	830	nM	CHEMBL4071622
6.04	IC50	920	nM	CHEMBL4088472
6.01	IC50	970	nM	CHEMBL4070102
5.96	IC50	1100	nM	CHEMBL4080496
5.96	IC50	1100	nM	CHEMBL4165785
5.89	IC50	1300	nM	CHEMBL4177474
5.80	IC50	1600	nM	CHEMBL4091488
5.80	IC50	1600	nM	CHEMBL4162337
5.72	IC50	1900	nM	CHEMBL4099717
5.72	IC50	1900	nM	CHEMBL4097731
5.68	IC50	2100	nM	CHEMBL4083000
5.66	IC50	2200	nM	CHEMBL4069550
5.64	IC50	2300	nM	CHEMBL4085751
5.62	IC50	2400	nM	CHEMBL4089075
5.57	IC50	2700	nM	CHEMBL4176640
5.30	IC50	5000	nM	CHEMBL4089069
5.27	Kd	5400	nM	CHEMBL4079731
5.16	IC50	6900	nM	CHEMBL4061441
5.08	IC50	8400	nM	CHEMBL4079326
5.05	IC50	8900	nM	CHEMBL4089547

PubChem BioAssay actives

52 with measured affinity, of 136 total; 43 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[4-[(3S)-4-(4-bromobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-5-methylpyrazol-1-yl]benzonitrile	1481958: Binding affinity to full-length human recombinant His6-tagged eIF4A3 expressed in Escherichia coli BL21(DE3) by surface plasmon resonance assay	kd	0.0430	uM
3-[5-[(3S)-4-(5-bromopyridine-2-carbonyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-2-oxo-1H-pyridin-3-yl]benzonitrile	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.0500	uM
(4-bromophenyl)-[(2S)-4-(6-bromopyrazolo[1,5-a]pyridine-3-carbonyl)-2-(4-chlorophenyl)piperazin-1-yl]methanone	1481958: Binding affinity to full-length human recombinant His6-tagged eIF4A3 expressed in Escherichia coli BL21(DE3) by surface plasmon resonance assay	kd	0.0570	uM
4-chloro-7-fluoro-6-propan-2-yl-1H-indole-2-carboxylic acid	1439864: Binding affinity to full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 expressed in Escherichia coli BL21(DE3) by isothermal titration calorimetric method	kd	0.0620	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148305: Binding affinity to human EIF4A3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0739	uM
3-[5-[(3S)-4-(5-bromopyridine-2-carbonyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-1-methyl-2-oxo-3-pyridinyl]benzonitrile	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.1000	uM
5-[(3S)-4-(5-bromopyridine-2-carbonyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-1-phenyl-3-[3-(trifluoromethyl)phenyl]pyridin-2-one	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.1400	uM
3-[5-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-2-oxo-1H-pyridin-3-yl]benzonitrile	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.1900	uM
[(2S)-4-(6-bromopyrazolo[1,5-a]pyridine-3-carbonyl)-2-(4-chlorophenyl)piperazin-1-yl]-(5-bromo-2-pyridinyl)methanone	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.2800	uM
4-[(3S)-4-(4-bromobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-2H-isoquinolin-1-one	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.2900	uM
5-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-3-(3-chlorophenyl)-1H-pyridin-2-one	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.2900	uM
3-[5-[4-(4-bromobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-1,3-oxazol-2-yl]benzonitrile	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.3600	uM
2-[5-[4-(4-bromobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-1,3-oxazol-2-yl]pyridine-4-carbonitrile	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.3900	uM
5-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-3-phenyl-1H-pyridin-2-one	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.4100	uM
(4-bromophenyl)-[4-(6-bromopyrazolo[1,5-a]pyridine-3-carbonyl)-2-(4-chlorophenyl)piperazin-1-yl]methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.4200	uM
5-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-3-(2-chlorophenyl)-1H-pyridin-2-one	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.4200	uM
5-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-3-(3-methylsulfonylphenyl)-1H-pyridin-2-one	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.4900	uM
3-[4-[4-(4-bromobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-5-methylpyrazol-1-yl]benzonitrile	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.5800	uM
3-[5-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-1,3-oxazol-2-yl]benzonitrile	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.6000	uM
(4-bromophenyl)-[2-(4-chlorophenyl)-4-(2-phenyl-1,3-oxazole-5-carbonyl)piperazin-1-yl]methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.6600	uM
5-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-3-[3-(trifluoromethyl)phenyl]-1H-pyridin-2-one	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.7000	uM
[4-(6-bromopyrazolo[1,5-a]pyridine-3-carbonyl)-2-(4-chlorophenyl)piperazin-1-yl]-(4-chlorophenyl)methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.7200	uM
5-[(3S)-4-(5-bromopyridine-2-carbonyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-1-methyl-3-[3-(trifluoromethyl)phenyl]pyridin-2-one	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.7500	uM
[4-(5-bromopyrazolo[1,5-a]pyridine-3-carbonyl)-2-(4-chlorophenyl)piperazin-1-yl]-(4-chlorophenyl)methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.8300	uM
(4-bromophenyl)-[2-(4-chlorophenyl)-4-(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)piperazin-1-yl]methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	0.9200	uM
(4-chlorophenyl)-[2-(4-chlorophenyl)-4-(pyrazolo[1,5-a]pyridine-3-carbonyl)piperazin-1-yl]methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	1.1000	uM
5-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-3-(4-chlorophenyl)-1H-pyridin-2-one	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	1.1000	uM
4-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-2H-isoquinolin-1-one	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	1.3000	uM
(4-chlorophenyl)-[2-(4-chlorophenyl)-4-(5-methyl-1-phenylpyrazole-4-carbonyl)piperazin-1-yl]methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	1.6000	uM
(4-bromophenyl)-[(2S)-2-(4-chlorophenyl)-4-(isoquinoline-4-carbonyl)piperazin-1-yl]methanone	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	1.6000	uM
4-chloro-6-propan-2-yl-1H-indole-2-carboxylic acid	1439857: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using 60 ug/ml single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	1.9000	uM
[4-(7-bromopyrazolo[1,5-a]pyridine-3-carbonyl)-2-(4-chlorophenyl)piperazin-1-yl]-(4-chlorophenyl)methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	1.9000	uM
2-[5-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-1,3-oxazol-2-yl]benzonitrile	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	2.1000	uM
(4-chlorophenyl)-[2-(4-chlorophenyl)-4-(2-phenyl-1,3-oxazole-5-carbonyl)piperazin-1-yl]methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	2.2000	uM
(4-chlorophenyl)-[2-(4-chlorophenyl)-4-(1H-indole-3-carbonyl)piperazin-1-yl]methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	2.3000	uM
(4-chlorophenyl)-[2-(4-chlorophenyl)-4-(1-phenylpyrazole-4-carbonyl)piperazin-1-yl]methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	2.4000	uM
(4-bromophenyl)-[(2S)-2-(4-chlorophenyl)-4-(quinoline-4-carbonyl)piperazin-1-yl]methanone	1492883: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	2.7000	uM
4-fluoro-6-propan-2-yl-1H-indole-2-carboxylic acid	1439857: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using 60 ug/ml single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	5.0000	uM
6-propan-2-yl-1H-indole-2-carboxylic acid	1439865: Binding affinity to full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 expressed in Escherichia coli BL21(DE3) administered for 60 to 120 secs by surface plasmon resonance biosensing assay	kd	5.4000	uM
7-fluoro-6-propan-2-yl-1H-indole-2-carboxylic acid	1439857: Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using 60 ug/ml single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	6.9000	uM
4-[5-[4-(4-chlorobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]-1,3-oxazol-2-yl]benzonitrile	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	8.4000	uM
[4-(4-bromopyrazolo[1,5-a]pyridine-3-carbonyl)-2-(4-chlorophenyl)piperazin-1-yl]-(4-chlorophenyl)methanone	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	8.9000	uM
3-[4-(4-bromobenzoyl)-3-(4-chlorophenyl)piperazine-1-carbonyl]pyrazolo[1,5-a]pyridine-6-carbonitrile	1481951: Inhibition of MLN51-induced full-length human recombinant His6-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using single stranded poly(U) RNA as substrate after 30 mins by ADP-Glo luminescence assay	ic50	9.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, affects cotreatment, increases expression	3
sodium arsenite	increases expression, increases localization	2
Tobacco Smoke Pollution	increases expression, decreases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
trichostatin A	affects expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
licochalcone B	increases expression	1
bisphenol AF	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1
Clozapine	affects cotreatment, decreases expression	1
Copper	affects binding, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Disulfiram	affects binding, decreases expression	1
Furaldehyde	affects cotreatment, affects localization, decreases expression, increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1

ChEMBL screening assays

26 unique, capped per target: 26 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4007297	Binding	Inhibition of MLN51-induced full length recombinant human N-terminal His6/SUMO-tagged eIF4A3 RNA dependent ATPase activity expressed in Escherichia coli BL21(DE3) using 60 ug/ml single stranded poly(U) RNA as substrate after 30 mins by ADP-	Discovery of selective ATP-competitive eIF4A3 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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