IDE

Summary

IDE (insulin degrading enzyme, HGNC:5381) is a protein-coding gene on chromosome 10q23.33, encoding Insulin-degrading enzyme (P14735). Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling.

This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein’s function are associated with Alzheimer’s disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.

Source: NCBI Gene 3416 — RefSeq curated summary.

At a glance

• GWAS associations: 22
• Clinical variants (ClinVar): 131 total
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004969

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5381
Approved symbol	IDE
Name	insulin degrading enzyme
Location	10q23.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000119912
Ensembl biotype	protein_coding
OMIM	146680
Entrez	3416

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 16 protein_coding, 14 retained_intron, 11 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000265986, ENST00000371581, ENST00000436178, ENST00000463640, ENST00000478361, ENST00000492362, ENST00000496903, ENST00000650060, ENST00000676540, ENST00000676626, ENST00000676816, ENST00000676987, ENST00000677079, ENST00000677096, ENST00000677193, ENST00000677196, ENST00000677434, ENST00000677569, ENST00000677953, ENST00000677978, ENST00000678026, ENST00000678082, ENST00000678097, ENST00000678248, ENST00000678410, ENST00000678458, ENST00000678673, ENST00000678715, ENST00000678824, ENST00000678844, ENST00000678977, ENST00000679069, ENST00000679089, ENST00000679174, ENST00000679222, ENST00000679232, ENST00000679304, ENST00000679312, ENST00000857320, ENST00000857321, ENST00000926841, ENST00000926842, ENST00000926843, ENST00000971392

RefSeq mRNA: 8 — MANE Select: NM_004969 NM_001165946, NM_001322793, NM_001322794, NM_001322795, NM_001322796, NM_001322797, NM_001410974, NM_004969

CCDS: CCDS53554, CCDS7421, CCDS91299, CCDS91300, CCDS91301

Canonical transcript exons

ENST00000265986 — 25 exons

Exon	Start	End
ENSE00001893153	92451684	92454539
ENSE00003463361	92463731	92464003
ENSE00003472980	92474841	92474961
ENSE00003480719	92508113	92508205
ENSE00003493344	92506442	92506522
ENSE00003496205	92534578	92534785
ENSE00003513908	92483255	92483337
ENSE00003516983	92470254	92470345
ENSE00003530878	92507575	92507666
ENSE00003556979	92468879	92468990
ENSE00003573870	92487196	92487318
ENSE00003576643	92456359	92456431
ENSE00003582944	92465676	92465843
ENSE00003587497	92510050	92510162
ENSE00003604775	92479277	92479421
ENSE00003622232	92508728	92508890
ENSE00003626360	92461191	92461252
ENSE00003629955	92490493	92490595
ENSE00003635720	92504794	92504897
ENSE00003646142	92531748	92531917
ENSE00003650499	92514920	92515042
ENSE00003655965	92475884	92475994
ENSE00003668022	92455576	92455643
ENSE00003669674	92537366	92537550
ENSE00003891074	92573922	92574093

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 97.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.8854 / max 159.4089, expressed in 1807 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110667	20.7841	1805
110666	1.9540	1250
110662	0.0438	3
110664	0.0416	17
110665	0.0342	4
110663	0.0238	3
205943	0.0039	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	97.28	gold quality
secondary oocyte	CL:0000655	96.50	gold quality
gluteal muscle	UBERON:0002000	96.09	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.71	gold quality
penis	UBERON:0000989	94.48	gold quality
triceps brachii	UBERON:0001509	94.22	gold quality
skin of leg	UBERON:0001511	93.86	gold quality
heart right ventricle	UBERON:0002080	93.67	gold quality
biceps brachii	UBERON:0001507	93.60	gold quality
zone of skin	UBERON:0000014	93.58	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.31	gold quality
oocyte	CL:0000023	93.10	gold quality
mammalian vulva	UBERON:0000997	92.91	gold quality
skin of abdomen	UBERON:0001416	92.80	gold quality
upper arm skin	UBERON:0004263	92.27	gold quality
nipple	UBERON:0002030	92.04	gold quality
pigmented layer of retina	UBERON:0001782	91.84	gold quality
gastrocnemius	UBERON:0001388	91.15	gold quality
muscle of leg	UBERON:0001383	91.00	gold quality
skeletal muscle tissue	UBERON:0001134	90.98	gold quality
calcaneal tendon	UBERON:0003701	90.85	gold quality
adrenal tissue	UBERON:0018303	90.82	gold quality
esophagus squamous epithelium	UBERON:0006920	90.79	gold quality
muscle organ	UBERON:0001630	90.57	gold quality
skeletal muscle organ	UBERON:0014892	90.56	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.26	gold quality
corpus epididymis	UBERON:0004359	90.26	gold quality
diaphragm	UBERON:0001103	89.40	silver quality
tendon	UBERON:0000043	89.26	gold quality
gingival epithelium	UBERON:0001949	89.23	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CNBP, IL13, IL4, NRF1, PPARG, PPARGC1A, STAT3, TBP, TGFB1, TNF

miRNA regulators (miRDB)

147 targeting IDE, 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-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6825-5P	99.96	69.81	3431

Literature-anchored findings (GeneRIF, showing 40)

• Insulin-degrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD). (PMID:11809755)
• IDE knockout mice show significantly elevated levels of blood insulin, brain beta-amyloid, and brain amyloid-precursor protein intracellular domain, providing key in vivo evidence that IDE degrades both extracellular and intracellular peptides. (PMID:12634421)
• analysis of over 2,400 samples provides no compelling evidence that variation in IDE contributes to diabetes susceptibility in humans (PMID:12716770)
• when intracellular long-chain fatty acid concentrations are elevated, they may act directly on insulin-degrading enzyme to decrease insulin metabolism and alter insulin action in intact cells and this mechanism may contribute to insulin resistance (PMID:12746301)
• Polymorphism in this enzyme are associated with NIDDM in men. (PMID:12765971)
• IDE gene polymorphisms do not confer susceptibility to early- or late-onset AD at least in a Japanese population. (PMID:14755451)
• Biochemical characteristics of insulin degradation in wound fluid were consistent with characteristics of insulin-degrading enzyme. Reduction in insulin-degrading activity in wound fluid is potential therapeutic target. (PMID:14764804)
• This study provides strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate Alzheimer’s disease phenotypes and risk for AD. (PMID:15024728)
• genomic region in the proximity of IDE that may contribute to Alzheimer and Parkinson disease in a similar manner. (PMID:15088150)
• IDE gene promoter region variants are associated with AD in subjects without an epsilon4 allele (PMID:15181249)
• Polymorphism in/near IDE contributes to a large proportion of variance in plasma insulin levels and correlated traits. (PMID:15277398)
• The C allele of single-nucleotide polymorphism IDE2 associated with Alzheimer disease. There may be a possible synergic interaction between IDE & APOE epsilon4. (PMID:15277615)
• IDE is targeted to mitochondria via alternative initiation of translation. (PMID:15285718)
• a defect in Abeta proteolysis by IDE contributes to the accumulation of this peptide in the cortical microvasculature (PMID:15489232)
• To test the hypothesis that insulin might upregulate IDE via a negative feedback control mechanism, we used both in vitro and in vivo strategies to determine the impact of insulin signaling on IDE levels. (PMID:15590928)
• Results indicate that alleles of IDE contribute to variability in A beta deposition in the AD brain and suggest that this relationship may have relevance for the degree of cognitive dysfunction in AD patients. (PMID:15718037)
• This study systematically characterizes IDE mRNAs, identifies a novel, catalytically inefficient splice form and compares its subcellular distribution, kinetic properties and ability to degrade amyloid beta protein to the known isoform. (PMID:15850385)
• Common genetic variation at IDE is unlikely to confer clinically significant risk of type 2 diabetes in Caucasians. (PMID:16380485)
• Beta-amyloid degradation is largely the result of the action of IDE, as it is blocked by insulin in the medium, a competitive substrate of IDE. IDE could be an important therapeutic target to decrease the amount of Abeta in the cerebrovasculature. (PMID:16511862)
• IDE-N is the catalytic domain and IDE-C facilitates substrate recognition as well as plays a key role in the oligomerization of IDE. (PMID:16574064)
• Different reconstructed insulin-degrading enzyme haplotypes were associated with Alzheimers disease and lower cognitive ability. (PMID:16675064)
• The combined genotype data from 1269 late-onset AD cases and 980 controls yielded a significant association to IDE_9 located in the 3’-end of the IDE gene after conservative multiple testing Bonferroni correction (p = 0.005). (PMID:16876916)
• protein structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon) (PMID:17051221)
• cellular receptor for infection by varicella-zoster virus. Interacts with VZV glycoprotein E. (PMID:17055432)
• First demonstration of IDE in normal and neoplastic human mammary tissues, providing an experimental starting point towards exploring a potential role of IDE in the control of tumor progression. (PMID:17143514)
• This study suggests IDE may be indirectly related to dementia via its regulation of insulin levels, but it is not a major gene for Alzheimer’s. (PMID:17192720)
• the genetic linkage of AD in this set of chromosome 10-linked AD families may be the result of systemic defects in IDE activity in the absence of altered IDE expression (PMID:17244626)
• SNPs rs4646953 & rs4646955 are associated with Alzheimer disease in Finnish patients, conferring an approximately two-fold increased risk. (PMID:17496198)
• Variations in IDE may contribute to diabetes susceptibility in the Korean population. (PMID:17913278)
• The single nucleotide polymorphism rs2209972 in the human IDE gene is associated with metabolic features of polycystic ovary syndrome women in a Chinese population. (PMID:17953957)
• This shows that IDE is involved in cellular insulin metabolism and provides further evidence that insulin inhibits protein degradation via an interaction with IDE. (PMID:17964527)
• Polymorphisms in the IDE-KIF11-HHEX gene locus are associated with susceptibility to type 2 diabetes across the boundary of race. (PMID:17971426)
• Importance of the distribution of the enzyme in brain and pituitary is discussed in relation to its main known substrataes. (PMID:18226493)
• the catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid beta peptide (PMID:18411275)
• Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans. (PMID:18448515)
• predict that alkylation of C812 and C819 disrupts substrate binding, whereas alkylation of C178 interferes with the apposition of active-site domains and subtly repositions zinc-binding residues (PMID:18621727)
• IDE protein was expressed in all the tissues assessed and all the tumor cell lines except for Raji and HL-60. (PMID:18783335)
• Insulin-degrading enzyme protein expression was found in normal tissues of the kidney, liver, lung, brain, breast and skeletal muscle, as well as in breast and ovarian cancer tissues. (PMID:18813847)
• kinetics and regulation of human IDE with short peptides (PMID:18986166)
• present study provides evidence that IDE promoter polymorphisms that significantly decrease IDE expression levels are associated with development of sporadic lzheimer disease (PMID:18996360)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ide	ENSDARG00000075570
mus_musculus	Ide	ENSMUSG00000056999
rattus_norvegicus	Ide	ENSRNOG00000016833
drosophila_melanogaster	Ide	FBGN0001247
caenorhabditis_elegans		WBGENE00013492
caenorhabditis_elegans		WBGENE00015360
caenorhabditis_elegans		WBGENE00018426

Paralogs (6): UQCRC1 (ENSG00000010256), NRDC (ENSG00000078618), PMPCB (ENSG00000105819), PITRM1 (ENSG00000107959), UQCRC2 (ENSG00000140740), PMPCA (ENSG00000165688)

Protein

Protein identifiers

Insulin-degrading enzyme — P14735 (reviewed: P14735)

Alternative names: Abeta-degrading protease, Insulin protease, Insulysin

All UniProt accessions (16): P14735, A0A3B3ISG5, A0A7I2V2P6, A0A7I2V2S1, A0A7I2V373, A0A7I2V3E3, A0A7I2V3K9, A0A7I2V4A4, A0A7I2V4Q3, A0A7I2V610, A0A7I2V612, A0A7I2V634, A0A7I2YQS6, A0A7I2YQV5, B3KSB8, R4GN65

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling. Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin. Contributes to the regulation of peptide hormone signaling cascades and regulation of blood glucose homeostasis via its role in the degradation of insulin, glucagon and IAPP. Plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia. Degrades the natriuretic peptides ANP, BNP and CNP, inactivating their ability to raise intracellular cGMP. Also degrades an aberrant frameshifted 40-residue form of NPPA (fsNPPA) which is associated with familial atrial fibrillation in heterozygous patients. Involved in antigen processing. Produces both the N terminus and the C terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to cytotoxic T lymphocytes by MHC class I. (Microbial infection) The membrane-associated isoform acts as an entry receptor for varicella-zoster virus (VZV).

Subunit / interactions. Homodimer. Can also form homotetramers. (Microbial infection) Interacts (via N-terminus) with varicella-zoster virus (VZV) envelope glycoprotein E (via N-terminus); the membrane-associated isoform may function as an entry receptor for this virus.

Subcellular location. Cytoplasm. Cytosol. Cell membrane. Secreted.

Tissue specificity. Detected in brain and in cerebrospinal fluid (at protein level).

Post-translational modifications. The N-terminus is blocked.

Activity regulation. Activated by small peptides. Activated by ATP and GTP, and to a lesser extent by CTP, TTP and PPPi. Inhibited by bacitracin. In vitro modification of Cys residues impairs enzyme activity.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. The SlyX motif may be involved in the non-conventional secretion of the protein.

Miscellaneous. ATP-binding induces a conformation change.

Similarity. Belongs to the peptidase M16 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P14735-1	1	yes
P14735-2	2

RefSeq proteins (8): NP_001159418, NP_001309722, NP_001309723, NP_001309724, NP_001309725, NP_001309726, NP_001397903, NP_004960* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001431	Pept_M16_Zn_BS	Binding_site
IPR007863	Peptidase_M16_C	Domain
IPR011249	Metalloenz_LuxS/M16	Homologous_superfamily
IPR011765	Pept_M16_N	Domain
IPR032632	Peptidase_M16_M	Domain
IPR050626	Peptidase_M16	Family
IPR054734	PqqF-like_C_4	Domain

Pfam: PF00675, PF05193, PF16187, PF22456

Enzyme classification (BRENDA):

• EC 3.4.24.56 — insulysin (BRENDA: 12 organisms, 277 substrates, 293 inhibitors, 87 Km, 99 kcat entries)

Substrate kinetics (BRENDA)

35 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ABZ-GGFLRKHGQ-EDDNP	0.0066–21.3	25
INSULIN	—	15
2-AMINOBENZOYL-GGFLRKHGQ-(N-(2,4-DINITROPHENYL)E	0.014–0.204	7
ABZ-GGFLRKHGQEDDNP	0.0059–0.0254	3
(7-METHOXYCOUMARIN-4-YL)ACETYL-KLVFFAEDK(DNP)-OH	0.0056–0.0076	2
7-METHOXYCOUMARIN-4-YL-ACETYL-RPPGFSAFK-2,4-DINI	0.0047–0.0049	2
AMYLOID BETA-PEPTIDE1-40	0.025–0.027	2
AMYLOID BETA-PROTEIN	0.0012–0.0025	2
DABCYL-TYR-GLU-VAL-HIS-HIS-GLN-LYS-LEU-VAL-PHE-P	1.2–2.3	2
PROINSULIN	0.0002–0.0009	2
(7-METHOXYCOUMARIN-4-YL)ACETYL-RPPGFSAFK(2,4-DIN	0.0099	1
ABZ-GLY-GLY-LEU-ARG-LYS-HIS-GLY-GLN-EDDNP	0.0111	1
ABZ-SEKKDNYIIKGV-NITROY-OH	0.219	1
AMYLOID BETA	0.08	1
AMYLOID BETA-PEPTIDE 1-40	0.0028	1

UniProt features (119 total): helix 45, strand 35, mutagenesis site 13, turn 7, binding site 7, sequence conflict 6, modified residue 2, chain 1, short sequence motif 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

62 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3CWW	X-RAY DIFFRACTION	1.96
2G47	X-RAY DIFFRACTION	2.1
2G56	X-RAY DIFFRACTION	2.2
4PES	X-RAY DIFFRACTION	2.21
4PFC	X-RAY DIFFRACTION	2.21
2G54	X-RAY DIFFRACTION	2.25
3E4Z	X-RAY DIFFRACTION	2.28
3E50	X-RAY DIFFRACTION	2.3
4PF7	X-RAY DIFFRACTION	2.33
3OFI	X-RAY DIFFRACTION	2.35
2G49	X-RAY DIFFRACTION	2.5
4PF9	X-RAY DIFFRACTION	2.5
2WK3	X-RAY DIFFRACTION	2.59
2G48	X-RAY DIFFRACTION	2.6
2WBY	X-RAY DIFFRACTION	2.6
3E4A	X-RAY DIFFRACTION	2.6
7K1F	X-RAY DIFFRACTION	2.6
4GSF	X-RAY DIFFRACTION	2.7
4LTE	X-RAY DIFFRACTION	2.71
4NXO	X-RAY DIFFRACTION	2.73
2JG4	X-RAY DIFFRACTION	2.8
2WC0	X-RAY DIFFRACTION	2.8
2YPU	X-RAY DIFFRACTION	2.8
7K1E	X-RAY DIFFRACTION	2.8
4GSC	X-RAY DIFFRACTION	2.81
4RE9	X-RAY DIFFRACTION	2.91
3HGZ	X-RAY DIFFRACTION	2.91
6BYZ	X-RAY DIFFRACTION	2.96
4GS8	X-RAY DIFFRACTION	2.99
2JBU	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14735-F1	94.06	0.93

Antibody-complex structures (SAbDab): 9 — 4IOF, 4M1C, 5CJO, 5UOE, 5WOB, 6B70, 6B7Z, 6BF7, 6BF9

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): 111 (proton acceptor)

Ligand- & substrate-binding residues (7): 108; 112; 189; 336–342 (in the exosite); 359–363; 429; 895–901

Post-translational modifications (2): 192, 697

Mutagenesis-validated functional residues (13):

Position	Phenotype
111	loss of catalytic activity.
132	increases catalytic rate towards ins and amyloid; when associated with c-817.
184	increases catalytic rate towards ins and amyloid; when associated with c-828.
286	reduced enzyme activity.
366–369	reduced enzyme activity.
426	increases catalytic rate towards ins and amyloid; when associated with c-899.
496	strongly reduced enzyme activity.
530	strongly increased enzyme activity.
767	decreases dimerization. no effect on degradation of anp. retains the ability to degrade an aberrant form of anp, when in
817	increases catalytic rate towards ins and amyloid; when associated with c-132.
828	increases catalytic rate towards ins and amyloid; when associated with c-184.
831	no effect on catalytic activity.
899	increases catalytic rate towards ins and amyloid; when associated with c-426.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases
R-HSA-77387	Insulin receptor recycling
R-HSA-9033241	Peroxisomal protein import

MSigDB gene sets: 303 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, ELVIDGE_HYPOXIA_DN, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_PROTEIN_BINDING, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEIN_BINDING, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOMF_METALLOPEPTIDASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE

GO Biological Process (19): proteolysis (GO:0006508), insulin receptor signaling pathway (GO:0008286), bradykinin catabolic process (GO:0010815), ubiquitin recycling (GO:0010992), antigen processing and presentation of endogenous peptide antigen via MHC class I (GO:0019885), protein catabolic process (GO:0030163), positive regulation of protein binding (GO:0032092), hormone catabolic process (GO:0042447), peptide catabolic process (GO:0043171), positive regulation of protein catabolic process (GO:0045732), negative regulation of proteolysis (GO:0045861), amyloid-beta metabolic process (GO:0050435), obsolete proteolysis involved in protein catabolic process (GO:0051603), amyloid-beta clearance (GO:0097242), amyloid-beta clearance by cellular catabolic process (GO:0150094), insulin metabolic process (GO:1901142), insulin catabolic process (GO:1901143), regulation of aerobic respiration (GO:1903715), symbiont entry into host cell (GO:0046718)

GO Molecular Function (21): amyloid-beta binding (GO:0001540), virus receptor activity (GO:0001618), endopeptidase activity (GO:0004175), metalloendopeptidase activity (GO:0004222), ATP binding (GO:0005524), zinc ion binding (GO:0008270), ATP hydrolysis activity (GO:0016887), beta-endorphin binding (GO:0031626), peptide binding (GO:0042277), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), insulin binding (GO:0043559), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), peptide hormone binding (GO:0017046), metal ion binding (GO:0046872)

GO Cellular Component (15): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), peroxisome (GO:0005777), peroxisomal matrix (GO:0005782), cytosol (GO:0005829), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), basolateral plasma membrane (GO:0016323), cytosolic proteasome complex (GO:0031597), extracellular exosome (GO:0070062), extracellular region (GO:0005576), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Deubiquitination	1
Signaling by Insulin receptor	1
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
catabolic process	4
binding	4
protein metabolic process	3
protein binding	3
protein catabolic process	2
peptidase activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
cellular homeostasis	1
antigen processing and presentation of peptide antigen via MHC class I	1
antigen processing and presentation of endogenous peptide antigen	1
macromolecule catabolic process	1
regulation of protein binding	1
positive regulation of binding	1
hormone metabolic process	1
peptide metabolic process	1
positive regulation of catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
metabolic process	1
multicellular organismal process	1
amyloid-beta metabolic process	1
amyloid-beta clearance	1
insulin metabolic process	1
aerobic respiration	1
regulation of cellular respiration	1
viral life cycle	1
symbiont entry into host	1
peptide binding	1
symbiont entry into host cell	1
exogenous protein binding	1
endopeptidase activity	1
metallopeptidase activity	1
adenyl ribonucleotide binding	1

Protein interactions and networks

STRING

1984 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IDE	INS	P01308	967
IDE	MMEL1	Q495T6	949
IDE	MME	P08473	941
IDE	APP	P05067	912
IDE	IAPP	P10997	845
IDE	ECE1	P42892	823
IDE	ECE2	P0DPD6	795
IDE	BACE1	P56817	794
IDE	PSEN1	P49768	770
IDE	SIRT4	Q9Y6E7	727
IDE	PMPCA	Q10713	702
IDE	PSEN2	P49810	684
IDE	APOE	P02649	667
IDE	PITRM1	Q5JRX3	640
IDE	NGB	Q9NPG2	619

IntAct

208 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
GFAP	NEFL	psi-mi:“MI:0914”(association)	0.850
VIM	NEFL	psi-mi:“MI:0914”(association)	0.840
GPKOW	DHX16	psi-mi:“MI:0914”(association)	0.820
SMNDC1	SF3B1	psi-mi:“MI:0914”(association)	0.790
HOXC9	AHCYL1	psi-mi:“MI:0914”(association)	0.640
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
MIA2	RGPD8	psi-mi:“MI:0914”(association)	0.640
RELT	OXSR1	psi-mi:“MI:0914”(association)	0.640
VWCE	HSPA5	psi-mi:“MI:0914”(association)	0.640
SIRT4	IDE	psi-mi:“MI:0914”(association)	0.620
CCL23	IDE	psi-mi:“MI:0915”(physical association)	0.590
APP	IDE	psi-mi:“MI:0915”(physical association)	0.560
RPGR	NPHP1	psi-mi:“MI:0914”(association)	0.560
VWCE	ZNF316	psi-mi:“MI:0914”(association)	0.530
MIA2	RGPD3	psi-mi:“MI:0914”(association)	0.530
SPINK2	STRN	psi-mi:“MI:0914”(association)	0.530
DEFB1	NMT2	psi-mi:“MI:0914”(association)	0.530
DKK4	LRP5	psi-mi:“MI:0914”(association)	0.530
SPINK7	UBB	psi-mi:“MI:0914”(association)	0.530
P3H3	HSPA8	psi-mi:“MI:0914”(association)	0.530
HLA-DPB1	IDE	psi-mi:“MI:0914”(association)	0.530
HYLS1	IDE	psi-mi:“MI:0914”(association)	0.530

BioGRID (265): UBC (Co-crystal Structure), UBC (Reconstituted Complex), NES (Reconstituted Complex), UBC (Biochemical Activity), IDE (Affinity Capture-MS), IDE (Affinity Capture-MS), IDE (Affinity Capture-MS), FAM98B (Co-fractionation), IDE (Co-fractionation), IDE (Co-fractionation), IDE (Co-fractionation), IDE (Co-fractionation), IDE (Co-fractionation), NAPRT (Co-fractionation), PAFAH1B2 (Co-fractionation)

ESM2 similar proteins: B0WSW8, F4HNU6, F4HTQ1, F4IDQ6, F4INY4, F4J3D9, O14077, O22941, O42908, P0DI12, P0DI13, P14735, P22817, P32898, P35559, P36009, P42789, P48053, P56523, P93834, Q06010, Q10040, Q10068, Q12496, Q16P87, Q24K02, Q26609, Q28BR5, Q2UGN1, Q42525, Q4WP38, Q54JQ2, Q5JRX3, Q5RDG3, Q61E36, Q655R6, Q6CWW6, Q6FUI7, Q6PF24, Q759T9

Diamond homologs: B8B0E2, F4HNU6, F4J3D9, O14077, O22941, O43847, P14735, P22817, P27508, P35559, P42789, P47245, Q06010, Q24K02, Q4WP38, Q5R4H6, Q69TY5, Q88QV3, Q8BHG1, Q9I2D2, Q9JHR7, P55174, Q10040, P40851, Q4W6B5, P45181, Q88A79, Q04805, Q40983, O05945, O32965, O86835, P0A5S9, P9WHT4, P9WHT5, Q00302, Q1RJ61, Q42290, Q4UML9, Q68XF0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IDE	“down-regulates quantity by destabilization”	INS	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 210 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
Chaperone Mediated Autophagy	5	18.4×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	105
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

4749 predictions. Top by Δscore:

Variant	Effect	Δscore
10:92454535:TCAGG:T	acceptor_gain	1.0000
10:92454536:CAGG:C	acceptor_gain	1.0000
10:92454536:CAGGC:C	acceptor_gain	1.0000
10:92454537:AGG:A	acceptor_gain	1.0000
10:92454538:GG:G	acceptor_gain	1.0000
10:92454538:GGCT:G	acceptor_loss	1.0000
10:92454540:C:CC	acceptor_gain	1.0000
10:92454541:T:A	acceptor_loss	1.0000
10:92455574:A:AC	donor_gain	1.0000
10:92455575:C:CC	donor_gain	1.0000
10:92461186:CTTA:C	donor_loss	1.0000
10:92461187:TTACC:T	donor_loss	1.0000
10:92461188:TAC:T	donor_loss	1.0000
10:92461189:A:AC	donor_gain	1.0000
10:92461189:AC:A	donor_gain	1.0000
10:92461190:C:A	donor_loss	1.0000
10:92461190:C:CT	donor_gain	1.0000
10:92461190:CC:C	donor_gain	1.0000
10:92461190:CCT:C	donor_gain	1.0000
10:92461190:CCTT:C	donor_gain	1.0000
10:92461248:GTTAT:G	acceptor_gain	1.0000
10:92461249:TTAT:T	acceptor_gain	1.0000
10:92461250:TAT:T	acceptor_gain	1.0000
10:92461252:TCTG:T	acceptor_loss	1.0000
10:92461253:C:CC	acceptor_gain	1.0000
10:92461253:CTG:C	acceptor_loss	1.0000
10:92461254:T:C	acceptor_loss	1.0000
10:92463726:CTTA:C	donor_loss	1.0000
10:92463728:TAC:T	donor_loss	1.0000
10:92463729:A:C	donor_loss	1.0000

AlphaMissense

6761 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:92456382:A:T	V958D	1.000
10:92456388:A:T	V956D	1.000
10:92463938:A:G	S852P	1.000
10:92463939:C:A	Q851H	1.000
10:92463939:C:G	Q851H	1.000
10:92463959:C:G	G845R	1.000
10:92463994:A:T	V833D	1.000
10:92464001:A:G	Y831H	1.000
10:92464003:C:A	G830V	1.000
10:92464003:C:T	G830D	1.000
10:92465676:C:A	G830C	1.000
10:92465676:C:G	G830R	1.000
10:92465693:C:G	R824P	1.000
10:92465694:G:T	R824S	1.000
10:92465696:A:G	L823P	1.000
10:92465704:G:C	F820L	1.000
10:92465704:G:T	F820L	1.000
10:92465706:A:G	F820L	1.000
10:92465735:A:G	L810P	1.000
10:92470270:C:A	G731V	1.000
10:92470270:C:T	G731E	1.000
10:92474874:A:G	W695R	1.000
10:92474874:A:T	W695R	1.000
10:92474912:G:T	A682D	1.000
10:92474924:G:T	P678H	1.000
10:92474938:G:C	F673L	1.000
10:92474938:G:T	F673L	1.000
10:92474940:A:G	F673L	1.000
10:92474941:A:C	N672K	1.000
10:92474941:A:T	N672K	1.000

dbSNP variants (sampled 300 via entrez): RS1000015730 (10:92559885 G>A,T), RS1000017365 (10:92514432 T>C), RS1000026378 (10:92513274 C>A,T), RS1000071119 (10:92560234 C>T), RS1000072128 (10:92514616 T>C), RS1000143616 (10:92513247 C>T), RS1000159276 (10:92508440 G>A), RS1000223963 (10:92478303 T>C), RS1000231721 (10:92555025 T>C), RS1000233004 (10:92548087 C>T), RS1000245667 (10:92533924 G>A), RS1000268146 (10:92564609 G>T), RS1000283678 (10:92548281 C>G,T), RS1000312669 (10:92570768 A>G), RS1000318805 (10:92566472 C>T)

Disease associations

OMIM: gene MIM:146680 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000712_21	Type 2 diabetes	1.000000e-15
GCST001621_19	Airflow obstruction	3.000000e-06
GCST002352_7	Type 2 diabetes	3.000000e-19
GCST003400_27	Type 2 diabetes	2.000000e-14
GCST003400_28	Type 2 diabetes	2.000000e-14
GCST003400_50	Type 2 diabetes	6.000000e-20
GCST003632_1	Survival in sporadic amyotrophic lateral sclerosis	2.000000e-09
GCST004131_111	Inflammatory bowel disease	5.000000e-07
GCST005047_13	Type 2 diabetes	2.000000e-19
GCST005047_79	Type 2 diabetes	7.000000e-13
GCST005047_95	Type 2 diabetes	5.000000e-12
GCST005146_12	Birth weight	1.000000e-14
GCST005413_11	Type 2 diabetes	3.000000e-09
GCST007847_35	Type 2 diabetes	5.000000e-39
GCST008159_41	Waist-to-hip ratio adjusted for BMI	8.000000e-06
GCST008362_194	Birth weight	4.000000e-23
GCST008916_68	Asthma	7.000000e-10
GCST009379_105	Type 2 diabetes	4.000000e-07
GCST009379_106	Type 2 diabetes	1.000000e-08
GCST009379_107	Type 2 diabetes	5.000000e-07
GCST010118_113	Type 2 diabetes	1.000000e-71
GCST010244_405	Triglyceride levels	3.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0000714	survival time
EFO:0004344	birth weight
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293287 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 622,059 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1200883	THONZONIUM BROMIDE	4	1,098
CHEMBL1201195	CEFMETAZOLE	4	10,281
CHEMBL1219	RABEPRAZOLE	4	12,441
CHEMBL857	BIOTIN	4	584,666
CHEMBL51085	EBSELEN	3	13,237
CHEMBL1237046	ROLITETRACYCLINE	2	336

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M16: Pitrilysin

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
NTE-1	Inhibition	8.4	pIC50
NTE-2	Inhibition	7.74	pIC50
quinoline 2	Inhibition	5.7	pIC50

Binding affinities (BindingDB)

10 measured of 39 human assays (39 total across all organisms); most potent 10 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(4Z,8S,11S,14R)-8-(3-amino-3-oxopropyl)-14-[(4-benzoylphenyl)methyl]-11-(cyclohexylmethyl)-3,6,9,12,15-pentaoxo-1,2,7,10,13,16,21-heptazacyclohexacos-4-ene-22-carboxylic acid	IC50	54 nM	US-9243038: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
(4Z,8S,11S,14R)-8-(3-amino-3-oxopropyl)-14-[(4-benzoylphenyl)methyl]-11-(cyclohexylmethyl)-N-ethyl-3,6,9,12,15-pentaoxo-1,2,7,10,13,16,21-heptazacyclopentacos-4-ene-22-carboxamide	IC50	60 nM	US-9243038: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
(3E,7S,10R,20S)-7-(3-aminobut-3-enyl)-13-[(4-benzoylphenyl)methyl]-10-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,6,12-triazacycloicos-3-ene-20-carboxamide	IC50	60 nM	US-9610322: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
(3R,6S,9S,12E)-9-(4-aminobutyl)-3-[(4-benzoylphenyl)methyl]-6-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,4,7,10,15-pentazacycloicos-12-ene-16-carboxamide	IC50	65 nM	US-9243038: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]-N-[3-[2-[2-[2-[(4Z,8S,11S,14R)-8-(3-amino-3-oxopropyl)-14-[(4-benzoylphenyl)methyl]-11-(cyclohexylmethyl)-3,6,9,12,15-pentaoxo-1,2,7,10,13,16,21-heptazacyclohexacos-4-en-22-yl]-2-oxoethoxy]ethoxy]ethoxy]propyl]pentanamide	IC50	80 nM	US-9243038: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
3-[(3R,6S,12E)-3-[(4-benzoylphenyl)methyl]-16-carbamoyl-6-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,4,7,10,15-pentazacycloicos-12-en-9-yl]propanoic acid	IC50	85 nM	US-9243038: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
(3E,7S,10R,20S)-13-[(4-benzoylphenyl)methyl]-10-(cyclohexylmethyl)-7-(cyclopropylmethyl)-2,5,8,11,14-pentaoxo-1,6,12-triazacycloicos-3-ene-20-carboxamide	IC50	1000 nM	US-9610322: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
(3E,7S,10R,20R)-13-[(4-benzoylphenyl)methyl]-7,10-bis(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,6,12-triazacycloicos-3-ene-20-carboxamide	IC50	1500 nM	US-9610322: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
(3E,7S,10R,20R)-7-(3-aminobut-3-enyl)-13-[(4-benzoylphenyl)methyl]-10-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,6,12-triazacycloicos-3-ene-20-carboxamide	IC50	5600 nM	US-9610322: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof
(3E,7S,10R)-13-[(4-benzoylphenyl)methyl]-10-(cyclohexylmethyl)-7-[3-(diaminomethylideneamino)propyl]-2,5,8,11,14-pentaoxo-1,6,12-triazacycloicos-3-ene-20-carboxamide	IC50	10000 nM	US-9610322: Macrocyclic insulin-degrading enzyme (IDE) inhibitors and uses thereof

ChEMBL bioactivities

154 potent at pChembl≥5 of 263 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.85	Ki	1.4	nM	CHEMBL2324206
8.77	Ki	1.7	nM	CHEMBL2324220
8.53	Ki	2.96	nM	CHEMBL2324220
8.40	IC50	4	nM	CHEMBL4437643
7.85	IC50	14	nM	EBSELEN
7.66	Ki	21.7	nM	CHEMBL2324220
7.66	Kd	22	nM	CHEMBL4211248
7.64	Ki	23.1	nM	CHEMBL2324207
7.59	Ki	25.9	nM	CHEMBL2324201
7.42	Ki	37.9	nM	CHEMBL2324220
7.38	IC50	42	nM	EBSELEN
7.36	Ki	43.7	nM	CHEMBL2324206
7.30	Ki	49.8	nM	CHEMBL2324204
7.30	IC50	50	nM	CHEMBL4556893
7.27	IC50	54	nM	CHEMBL3980383
7.25	IC50	56	nM	CHEMBL4241044
7.25	IC50	56	nM	CHEMBL4527561
7.22	IC50	60	nM	CHEMBL3986116
7.22	IC50	60	nM	CHEMBL4108142
7.22	IC50	60	nM	CHEMBL4113567
7.22	IC50	60	nM	CHEMBL4109327
7.22	IC50	60	nM	CHEMBL4108344
7.22	IC50	60	nM	CHEMBL4241044
7.22	IC50	60	nM	CHEMBL6062354
7.19	IC50	65	nM	CHEMBL4110918
7.15	Ki	70.3	nM	CHEMBL2324201
7.13	Ki	73.3	nM	CHEMBL2324209
7.11	Ki	78	nM	CHEMBL2324219
7.10	IC50	80	nM	CHEMBL3893930
7.07	Ki	85.1	nM	CHEMBL2324205
7.07	IC50	85	nM	CHEMBL4108429
7.06	Ki	87	nM	CHEMBL2324203
7.00	IC50	100	nM	CHEMBL3235416
7.00	IC50	100	nM	CHEMBL3925351
6.99	Ki	103	nM	CHEMBL2324202
6.97	Ki	107	nM	CHEMBL2324203
6.82	IC50	150	nM	CHEMBL4115434
6.77	Ki	171	nM	CHEMBL2324207
6.64	Ki	228	nM	CHEMBL2324204
6.61	Ki	246	nM	CHEMBL2324207
6.56	Ki	275	nM	CHEMBL2324201
6.48	IC50	330	nM	CHEMBL4241044
6.44	Ki	365	nM	CHEMBL2324205
6.43	IC50	370	nM	CHEMBL4112829
6.39	Ki	410	nM	CHEMBL2324206
6.30	Ki	498	nM	CHEMBL2324213
6.30	IC50	500	nM	CHEMBL4109006
6.28	EC50	530	nM	CHEMBL3235416
6.24	IC50	570	nM	CHEMBL3972636
6.24	IC50	570.7	nM	CHEMBL3212590

PubChem BioAssay actives

61 with measured affinity, of 187 total; 35 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
5-[2-[[(4S)-4-acetamido-5-[[(2R)-1-[benzoyl-[(2R)-1-[[(2R)-1-(hydroxyamino)-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-oxopentanoyl]amino]ethylamino]naphthalene-1-sulfonic acid	729332: Inhibition of human recombinant IDE-mediated fluorescein-Abeta-(1-40)-Lys-biotin degradation	ki	0.0014	uM
(4S)-5-amino-4-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2R)-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxopentanoic acid	1600071: Inhibition of human recombinant IDE expressed in CHO cells in presence of [125I]-insulin by HTRF assay	ki	0.0017	uM
methyl N-[(2S)-2-[4-[5-[4-[[(2S)-2-[(3S)-3-amino-2-oxopiperidin-1-yl]-2-cyclohexylacetyl]amino]phenyl]pentoxy]phenyl]-3-quinolin-3-ylpropyl]carbamate	1600074: Inhibition of recombinant IDE exosite (unknown origin) expressed in Escherichia coli using insulin as substrate incubated for 4 hrs by AlphaLisa assay	ic50	0.0040	uM
2-phenyl-1,2-benzoselenazol-3-one	1600086: Inhibition of human recombinant IDE expressed in Escherichia coli BL21 (DE3) cells using insulin as substrate preincubated for 10 mins followed by substrate addition and measured after 15 mins by fluorescence based assay	ic50	0.0140	uM
(4S)-4-acetamido-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(3R,12S,17S,20S,23S)-17-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[(2-amino-2-oxoethyl)amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamoyl]-20-(2-carboxyethyl)-2,8,11,14,19,22-hexaoxo-1,7,10,15,18,21-hexazatricyclo[21.3.0.03,7]hexacosan-12-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	1386258: Binding affinity to IDE E111Q mutant (unknown origin) using N-terminal FITC-labeled compound after 2 hrs in absence of light at 298 K by fluorescence polarization assay	kd	0.0220	uM
2-[(2R,5R,8R,11R,14R,17R)-8-benzyl-11-[(2R)-butan-2-yl]-17-[[(2R)-1-[[(2R)-5-carbamimidamido-1-[[(2R)-1-(hydroxyamino)-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]carbamoyl]-14-(3-carbamimidamidopropyl)-5-(1H-imidazol-5-ylmethyl)-3,6,9,12,15,20-hexaoxo-1,4,7,10,13,16-hexazacycloicos-2-yl]acetic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0231	uM
(4S)-5-amino-4-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2R,3S)-3-hydroxy-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0259	uM
(4R)-4-amino-5-[[(2R)-1-[[(2R)-5-(diaminomethylideneamino)-1-[[(2R)-1-(hydroxyamino)-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0498	uM
(3R,6S,9S,12E,16S)-9-(4-aminobutyl)-3-[(4-benzoylphenyl)methyl]-6-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,4,7,10,15-pentazacycloicos-12-ene-16-carboxamide	1625401: Inhibition of IDE (unknown origin) assessed as cleavage of Mca-RPPGFSAFK(Dnp)-OH by fluorescence assay	ic50	0.0500	uM
4-fluoro-N-[[3-[(2R)-4-(hydroxyamino)-1-naphthalen-2-yl-4-oxobutan-2-yl]-1,2-dihydrotriazol-5-yl]methyl]benzamide	1559627: Inhibition of human recombinant IDE pre-incubated for 10 mins before Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp substrate addition and measured after 30 mins by fluorescence based assay	ic50	0.0560	uM
4-fluoro-N-[[1-[(2R)-4-(hydroxyamino)-1-naphthalen-2-yl-4-oxobutan-2-yl]triazol-4-yl]methyl]benzamide	1396210: Inhibition of human IDE using insulin as substrate preincubated for 10 mis followed by substrate addition and measured after 30 mins	ic50	0.0560	uM
(4S)-5-amino-4-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2S)-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0733	uM
(4S)-4-acetamido-5-[[(2S)-1-[[(4S,6S)-1-(diaminomethylideneamino)-8-(hydroxyamino)-6-(naphthalen-2-ylmethyl)-5,8-dioxooctan-4-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0780	uM
(4R)-4-amino-5-[[(2R)-1-[[(2R)-5-(diaminomethylideneamino)-1-[[(2R)-1-(hydroxyamino)-3-naphthalen-2-yl-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0851	uM
prop-2-enyl (2S)-5-(diaminomethylideneamino)-2-[[(2R)-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoate	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.0870	uM
2-[[2-[[(2S)-3-(1H-imidazol-5-yl)-1-(methylamino)-1-oxopropan-2-yl]amino]-2-oxoethyl]-(3-phenylpropyl)amino]acetic acid	1127273: Inhibition of human recombinant IDE-mediated amyloid beta (16 to 23) hydrolysis using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins measured after 30 mins by spectrophotometer analysis	ic50	0.1000	uM
(4S)-5-amino-4-[[(2S)-2-[[(2S)-5-(diaminomethylideneamino)-2-[[(2R,3R)-3-hydroxy-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-oxopentanoic acid	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.1030	uM
(2R,3R)-N-[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-N’,3-dihydroxy-2-(naphthalen-2-ylmethyl)butanediamide	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	0.4980	uM
2-[benzyl-[2-[[(2S)-3-(1H-imidazol-5-yl)-1-(methylamino)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]acetic acid	1127273: Inhibition of human recombinant IDE-mediated amyloid beta (16 to 23) hydrolysis using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins measured after 30 mins by spectrophotometer analysis	ic50	0.6000	uM
2-[[2-[[(2S)-3-(1H-imidazol-5-yl)-1-methoxy-1-oxopropan-2-yl]amino]-2-oxoethyl]-(3-phenylpropyl)amino]acetic acid	1127273: Inhibition of human recombinant IDE-mediated amyloid beta (16 to 23) hydrolysis using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins measured after 30 mins by spectrophotometer analysis	ic50	0.6000	uM
(2R)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-N’-hydroxy-2-(naphthalen-2-ylmethyl)butanediamide	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	1.1500	uM
2-[[2-[[(2S)-3-(1H-imidazol-5-yl)-1-methoxy-1-oxopropan-2-yl]amino]-2-oxoethyl]-(2-phenylethyl)amino]acetic acid	1127273: Inhibition of human recombinant IDE-mediated amyloid beta (16 to 23) hydrolysis using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins measured after 30 mins by spectrophotometer analysis	ic50	1.4000	uM
2-[benzyl-[2-[[(2S)-3-(1H-imidazol-5-yl)-1-methoxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]acetic acid	1127273: Inhibition of human recombinant IDE-mediated amyloid beta (16 to 23) hydrolysis using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins measured after 30 mins by spectrophotometer analysis	ic50	2.9000	uM
N-(3-imidazol-1-ylpropyl)-4-(1-thiophen-2-ylsulfonylindol-3-yl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	5.0119	uM
prop-2-enyl (2S)-5-(diaminomethylideneamino)-2-[[(2S)-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]amino]pentanoate	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	5.2800	uM
4-[1-(4-fluorophenyl)sulfonylindol-3-yl]-N-(3-imidazol-1-ylpropyl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	6.7608	uM
(6R,7S)-7-[[2-(cyanomethylsulfanyl)acetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid	1600069: Inhibition of human recombinant IDE expressed in Escherichia coli BL21 (DE3) cells using ATTO 655- Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate preincubated for 10 mins followed by substrate addition and measured after 30 mins by spectrophotometric analysis	ic50	7.0000	uM
(2R,3R)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-N’,3-dihydroxy-2-(naphthalen-2-ylmethyl)butanediamide	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	7.0200	uM
5-[1-(benzenesulfonyl)indol-3-yl]-N-(3-imidazol-1-ylpropyl)pentanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	7.2444	uM
(2R,3S)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-N’,3-dihydroxy-2-(naphthalen-2-ylmethyl)butanediamide	729333: Inhibition of human recombinant IDE-mediated FRET1 degradation	ki	7.7500	uM
4-[1-(2-fluorophenyl)sulfonylindol-3-yl]-N-(3-imidazol-1-ylpropyl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	7.9433	uM
4-[1-(benzenesulfonyl)indol-3-yl]-N-(4-imidazol-1-ylbutyl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	8.1283	uM
4-[1-(benzenesulfonyl)indol-2-yl]-N-(3-imidazol-1-ylpropyl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	8.1283	uM
(2S)-2-[bis(1H-imidazol-5-ylmethyl)amino]-5-(3-naphthalen-2-yl-5-sulfanylidene-1H-1,2,4-triazol-4-yl)pentanoic acid	1935861: Inhibition of recombinant human IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate measured after 45 mins by fluorescence assay	ic50	9.1000	uM
N-(3-imidazol-1-ylpropyl)-4-(1H-indol-3-yl)butanamide	1899291: Activation of human recombinant IDE using ATTO 655-Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-trp as substrate incubated for 10 mins followed by substrate addition and measured after 20 mins by fluorescence spectrophotometer analysis	ec50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression, decreases expression	4
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	decreases methylation, affects expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression, increases expression	1
3,4-dihydroxyphenylpropionic acid	affects activity, affects binding	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
tetrabromobisphenol A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
scopolin	affects activity, affects binding	1
2-chloro-5-nitrobenzanilide	decreases reaction, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
thifluzamide	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
isopraeroside IV	affects activity, affects binding	1
Bortezomib	increases expression	1
Rosiglitazone	decreases reaction, increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Arsenic	increases abundance, decreases expression	1

ChEMBL screening assays

68 unique, capped per target: 66 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614462	Functional	PUBCHEM_BIOASSAY: Dose Response: Fluorescence polarization-based cell-based high throughput dose response assay for inhibitors of insulin-degrading enzyme (IDE). (Class of assay: confirmatory) [Related pubchem assays: 434962 (Primary screen	PubChem BioAssay data set
CHEMBL1794358	Binding	PUBCHEM_BIOASSAY: Counterscreen for IDE activators: Fluorescence polarization-based biochemical high throughput dose response assay for activators of recombinant IDE. (Class of assay: confirmatory) [Related pubchem assays (depositor defined	PubChem BioAssay data set

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1U4	Abcam HeLa IDE KO	Cancer cell line	Female
CVCL_SR99	HAP1 IDE (-) 1	Cancer cell line	Male
CVCL_SS00	HAP1 IDE (-) 2	Cancer cell line	Male
CVCL_SS01	HAP1 IDE (-) 3	Cancer cell line	Male
CVCL_SS02	HAP1 IDE (-) 4	Cancer cell line	Male
CVCL_YB06	EndoC-betaH1 IDE-KO	Transformed cell line	Female

Clinical trials (associated diseases)

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