MME

Summary

MME (membrane metalloendopeptidase, HGNC:7154) is a protein-coding gene on chromosome 3q25.2, encoding Neprilysin (P08473). Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids.

The protein encoded by this gene is a type II transmembrane glycoprotein and a common acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). The encoded protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL. This protein is not restricted to leukemic cells, however, and is found on a variety of normal tissues. The protein is a neutral endopeptidase that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin.

Source: NCBI Gene 4311 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease axonal type 2T (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 809 total — 59 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_007289

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7154
Approved symbol	MME
Name	membrane metalloendopeptidase
Location	3q25.2
Locus type	gene with protein product
Status	Approved
Aliases	CALLA, CD10, NEP
Ensembl gene	ENSG00000196549
Ensembl biotype	protein_coding
OMIM	120520
Entrez	4311

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 26 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000360490, ENST00000382989, ENST00000460393, ENST00000462745, ENST00000473730, ENST00000477669, ENST00000491026, ENST00000491597, ENST00000492661, ENST00000493237, ENST00000493888, ENST00000495577, ENST00000615825, ENST00000675418, ENST00000679362, ENST00000680057, ENST00000680282, ENST00000871479, ENST00000871480, ENST00000871481, ENST00000871482, ENST00000871483, ENST00000871484, ENST00000871485, ENST00000915239, ENST00000915240, ENST00000915241, ENST00000915242, ENST00000915243, ENST00000915244, ENST00000944233

RefSeq mRNA: 7 — MANE Select: NM_007289 NM_000902, NM_001354642, NM_001354643, NM_001354644, NM_007287, NM_007288, NM_007289

CCDS: CCDS3172, CCDS87157

Canonical transcript exons

ENST00000360490 — 23 exons

Exon	Start	End
ENSE00000779814	155172117	155172212
ENSE00000779815	155168732	155168797
ENSE00000779819	155148550	155148653
ENSE00000934032	155116479	155116559
ENSE00000934033	155116664	155116759
ENSE00000934034	155116868	155116986
ENSE00000934035	155118746	155118811
ENSE00000934036	155140191	155140292
ENSE00000934037	155141991	155142127
ENSE00000934038	155142237	155142330
ENSE00000934039	155143443	155143571
ENSE00000934040	155144359	155144457
ENSE00000934041	155147144	155147224
ENSE00001019488	155138102	155138236
ENSE00001019489	155085059	155085094
ENSE00001513376	155080319	155080466
ENSE00003471746	155084158	155084327
ENSE00003507214	155168492	155168625
ENSE00003599031	155160390	155160448
ENSE00003614810	155172536	155172612
ENSE00003662973	155166902	155167021
ENSE00003790302	155114994	155115155
ENSE00003903792	155180360	155183704

Expression profiles

Bgee: expression breadth ubiquitous, 212 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.8128 / max 2274.1665, expressed in 1343 samples.

FANTOM5 promoters (29 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39364	10.3752	1009
39362	8.8135	871
39375	7.0334	776
39365	4.2446	692
39376	3.4666	632
39368	2.3775	636
39366	2.2854	617
39361	1.7353	587
39360	1.6730	436
39363	1.5129	475

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.47	gold quality
renal glomerulus	UBERON:0000074	99.34	gold quality
metanephric glomerulus	UBERON:0004736	99.32	gold quality
stromal cell of endometrium	CL:0002255	98.84	gold quality
kidney epithelium	UBERON:0004819	98.02	gold quality
duodenum	UBERON:0002114	96.82	gold quality
nephron tubule	UBERON:0001231	96.13	gold quality
adult mammalian kidney	UBERON:0000082	95.43	gold quality
sural nerve	UBERON:0015488	94.69	gold quality
ileal mucosa	UBERON:0000331	94.65	gold quality
blood	UBERON:0000178	94.11	gold quality
kidney	UBERON:0002113	93.67	gold quality
olfactory bulb	UBERON:0002264	92.92	gold quality
tibial nerve	UBERON:0001323	92.36	gold quality
mammary duct	UBERON:0001765	92.07	gold quality
epithelium of mammary gland	UBERON:0003244	91.71	gold quality
mammary gland	UBERON:0001911	91.11	gold quality
thoracic mammary gland	UBERON:0005200	91.03	gold quality
endometrium	UBERON:0001295	90.64	gold quality
metanephros	UBERON:0000081	90.47	gold quality
placenta	UBERON:0001987	90.29	gold quality
subcutaneous adipose tissue	UBERON:0002190	89.88	gold quality
prostate gland	UBERON:0002367	89.80	gold quality
gluteal muscle	UBERON:0002000	89.39	gold quality
cortex of kidney	UBERON:0001225	89.38	gold quality
right lung	UBERON:0002167	89.08	gold quality
adipose tissue	UBERON:0001013	88.98	gold quality
small intestine	UBERON:0002108	88.95	gold quality
trigeminal ganglion	UBERON:0001675	88.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.73	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	1495.39
E-GEOD-114530	yes	1368.62
E-GEOD-100618	yes	694.34
E-MTAB-10287	yes	299.29
E-CURD-79	yes	265.49
E-CURD-119	yes	69.40
E-HCAD-4	yes	52.11
E-CURD-112	yes	48.47
E-HCAD-6	yes	43.90
E-HCAD-10	yes	22.79
E-MTAB-9067	yes	18.25
E-ANND-3	yes	14.90
E-HCAD-24	no	584.65
E-MTAB-10290	no	222.69
E-CURD-11	no	119.01

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): APP, AR, BCL6, CEBPA, CTNNB1, ESR1, ESR2, HDAC1, HIF1A, HNF4A, HOXC6, IRF6, MYC, NFKB, SP1, SPI1

miRNA regulators (miRDB)

156 targeting MME, 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-4533	100.00	69.48	2758
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AT-5P	99.96	70.83	2666
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-493-5P	99.96	72.47	2382
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505

Literature-anchored findings (GeneRIF, showing 40)

• Toward an optimal joint recognition of the S1’ subsites of endothelin converting enzyme-1 (ECE-1), angiotensin converting enzyme (ACE), and neutral endopeptidase (NEP). (PMID:11906289)
• stromal expression of CD10 in breast cancer is an important novel prognostic factor (PMID:12070597)
• a marker for cycling cells with propensity for apoptosis in childhood ALL (PMID:12087466)
• expressed at high levels in sebaceous glands of acne patients (PMID:12102663)
• Abeta 42-induced increase in neprilysin is associated with prevention of amyloid plaque formation in vivo (PMID:12105192)
• CD10 antigen is upregulated during the process of metastasis in melanomas. It is rare in primary melanomas. (PMID:12140380)
• role of two C-terminal cysteines in proper folding (PMID:12150966)
• CD10 expression is an integral part of colorectal carcinogenesis and seems to contribute to the invasion and thus probably facilitates metastasis (PMID:12203213)
• Expression declines in Alzheimer disease vasculature; possibly involved in cerebral amyloid angiopathy (PMID:12387451)
• CD10 expression in hematopoitic cells denotes commitment to B-cell and natural killer cells lineages. (PMID:12393702)
• CD5-negative, CD10-negative small B-cell leukemia: variant of chronic lymphocytic leukemia or a distinct entity (PMID:12447961)
• elevated neutral endopeptidase activity in the skin and chronic ulcers of subjects with diabetes combined with peripheral neuropathy may contribute to deficient neuroinflammatory signaling and may impair wound healing in subjects with diabetes. (PMID:12485446)
• no association between polymorphisms in the promoter region and Swedish Alzheimer’s disease patients (PMID:12527400)
• In transgenic mouse models of amyloidosis, unilateral intracerebral injection of Lenti-Nep reduced amyloid-beta deposits and ameliorated neurodegenerative alterations in the frontal cortex and hippocampus (PMID:12657655)
• nep gene polymorphism is associated with cerebral amyloid angiopathy. (PMID:12754344)
• The modulator effect of vitamin E and C on NEP membrane enzyme activity after exposure to fatty acid stimulation suggests that lipid oxidation may activate NEP. (PMID:12785004)
• Independent signals determine the subcellular localization of NEP in prostate cancer cells (PMID:14550292)
• Activity of NEP in prostate cancer cells is regulated by bombesin and il-1beta with IL-1beta acting as modulator of cellular differentiation. (PMID:14673956)
• the GT-repeat polymorphism in the promoter region of the neprilysin gene or some other unknown polymorphisms, which are in a linkage disequilibrium, confer a susceptibility to late-onset Alzheimer’s disease (PMID:14739539)
• x-ray crystallographic study of neprilysin (PMID:14747736)
• Gene transfer of human neprilysin abolished the increase in Abeta levels in the hippocampus of neprilysin-deficient mice and also reduced the increase in young mutant amyloid precursor protein transgenic mice and to retard development of amyloid pathology (PMID:14749444)
• CD10 has a role in preventing proliferation or differentiation of non-neoplastic and neoplastic hepatocytes (PMID:14767532)
• NEP mRNA and protein are expressed mainly by the epithelial cells and to a minor extent by the stromal cells of human prostate glands. (PMID:14968440)
• endogenous targeting signal in wild-type neprilysin is well optimized for the overall neuronal clearance of Abeta (PMID:15100223)
• CD10 expression was found significantly higher in metastatic than in primary tumors. (PMID:15205682)
• decreased NEP expression might contribute to progression of prostate cancer; methylation is an important mechanism of NEP protein silencing (PMID:15217945)
• We have examined the kinetics of angiotensin peptide cleavage by full-length human ACE, the separate N- and C-domains of ACE, the homologue of ACE, ACE2, and NEP (neprilysin). (PMID:15283675)
• Statistical analysis showed significant association of CD10-positive tumors with clinicopathologic aggressiveness and mitotic figures. (PMID:15286660)
• A three-dimensional model of the neprilysin 2 active site based on the X-ray structure of neprilysin. (PMID:15294904)
• truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal membranous glomerulopathies. (PMID:15464186)
• CD10-stained bile canalicular pattern becomes increasingly reduced with the advance of fibrosis or the presence of severe lobular inflammation or extensive metastases (PMID:15469471)
• CD10 was found in the majority of clear cell renal cell carcinomas. (PMID:15502805)
• CD10 is a superior marker for distinguishing between a hemangioblastoma and a metastatic clear cell renal cell carcinoma. (PMID:15578072)
• CD10 positivity was associated with an excellent 8-year overall survival in the low-risk IPI (International Prognostic Index) patients. (PMID:15720419)
• Expressed in a case of microvillous atrophy. (PMID:15785408)
• Genetic variation close to Neprilysin gene may influence the susceptibility to Alzheimer disease in Chinese population. (PMID:15860464)
• Dexamethasone is a potent modulator of NEP on immature B-lymphocytes. (PMID:15870909)
• Results conclude that CD10 has limited value in confirming the diagnosis of primary conventional renal-cell adenocarcinoma because of its low specificity. (PMID:15945081)
• data identify CD10- cytoplasmic immunoglobulin-positive pre-B ALL as a rare (2.2%) but distinct immuno-subtype of adult ALL that is characterized by a high MLL rearrangement rate and a worse outcome (PMID:16123216)
• Significant decrease in neprilysin mRNA levels in both Alzheimer’s disease and normal elderly subjects with amyloid plaques compared to control cases was found. (PMID:16226260)

Cross-species orthologs

25 orthologs

Organism	Symbol	Gene ID
danio_rerio	kel	ENSDARG00000076950
mus_musculus	Mme	ENSMUSG00000027820
rattus_norvegicus	Mme	ENSRNOG00000009514
drosophila_melanogaster	Nepl21	FBGN0027578
drosophila_melanogaster	Nep3	FBGN0031081
drosophila_melanogaster	Nepl3	FBGN0031678
drosophila_melanogaster	Nepl12	FBGN0037727
drosophila_melanogaster	Nep4	FBGN0038818
drosophila_melanogaster	Nepl15	FBGN0039024
drosophila_melanogaster	Nep7	FBGN0039564
drosophila_melanogaster	Nepl18	FBGN0039611
drosophila_melanogaster	Nepl19	FBGN0039612
drosophila_melanogaster	Nepl20	FBGN0039613
caenorhabditis_elegans		WBGENE00013785
caenorhabditis_elegans		WBGENE00013786
caenorhabditis_elegans		WBGENE00013926
caenorhabditis_elegans		WBGENE00016778
caenorhabditis_elegans		WBGENE00016896
caenorhabditis_elegans		WBGENE00017550
caenorhabditis_elegans		WBGENE00017553
caenorhabditis_elegans		WBGENE00017554
caenorhabditis_elegans		WBGENE00017555
caenorhabditis_elegans		WBGENE00018196
caenorhabditis_elegans		WBGENE00018227
caenorhabditis_elegans		WBGENE00020293

Paralogs (6): PHEX (ENSG00000102174), ECE1 (ENSG00000117298), MMEL1 (ENSG00000142606), ECE2 (ENSG00000145194), ECEL1 (ENSG00000171551), KEL (ENSG00000197993)

Protein

Protein identifiers

Neprilysin — P08473 (reviewed: P08473)

Alternative names: Atriopeptidase, Common acute lymphocytic leukemia antigen, Enkephalinase, Neutral endopeptidase 24.11, Skin fibroblast elastase

All UniProt accessions (6): A0A6Q8PFY6, A0A7I2U302, C9IYX7, C9JDZ3, P08473, Q3KQS6

UniProt curated annotations — full annotation on UniProt →

Function. Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids. Biologically important in the destruction of opioid peptides such as Met- and Leu-enkephalins by cleavage of a Gly-Phe bond. Catalyzes cleavage of bradykinin, substance P and neurotensin peptides. Able to cleave angiotensin-1, angiotensin-2 and angiotensin 1-9. Involved in the degradation of atrial natriuretic factor (ANF) and brain natriuretic factor (BNP(1-32)). Displays UV-inducible elastase activity toward skin preelastic and elastic fibers.

Subcellular location. Cell membrane.

Post-translational modifications. Myristoylation is a determinant of membrane targeting. Glycosylation at Asn-628 is necessary both for surface expression and neutral endopeptidase activity.

Disease relevance. Charcot-Marie-Tooth disease, axonal, type 2T (CMT2T) [MIM:617017] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry. Spinocerebellar ataxia 43 (SCA43) [MIM:617018] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA43 is a slowly progressive, autosomal dominant form. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited in a dose dependent manner by opiorphin. Activated by K49-P1-20, a twenty-residue synthetic peptide shortened from the snake B.asper myotoxin II.

Cofactor. Binds 1 zinc ion per subunit.

Miscellaneous. Important cell surface marker in the diagnostic of human acute lymphocytic leukemia.

Similarity. Belongs to the peptidase M13 family.

RefSeq proteins (7): NP_000893, NP_001341571, NP_001341572, NP_001341573, NP_009218, NP_009219, NP_009220* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000718	Peptidase_M13	Family
IPR008753	Peptidase_M13_N	Domain
IPR018497	Peptidase_M13_C	Domain
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR042089	Peptidase_M13_dom_2	Homologous_superfamily

Pfam: PF01431, PF05649

Enzyme classification (BRENDA):

• EC 3.4.24.11 — neprilysin (BRENDA: 14 organisms, 260 substrates, 217 inhibitors, 150 Km, 77 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
D-ALA2-LEU5-ENKEPHALIN	0.07–2.137	7
N-(4-CARBOXY-1-OXOBUTYL)-L-ALANYL-L-ALANYL-N-(4-	0.011–0.087	7
BRADYKININ	0.005–0.162	5
SUBSTANCE P	0.01–0.19	5
AMYLOID BETA PEPTIDE1-40	0.014–0.104	4
SUCCINYL-ALA-ALA-PHE-4-METHYLCOUMARIN 7-AMIDE	0.043–0.073	4
ANGIOTENSIN I	0.0004–34.1	3
MET-ENKEPHALIN	0.022–0.1	3
NEUROTENSIN	0.016–0.078	3
TYR-D-ALA-GLY-PHE-MET-NH2	0.061–0.32	3
(7-METHOXYCOUMARIN-4-YL)ACETYL-ARG-PRO-PRO-GLY-P	0.0068–0.0224	2
GASTRIN G-17	0.049–0.068	2
LEU-ENKEPHALIN	0.074–0.2	2
TYR-D-ALA-GLY-PHE-LEU	0.018–0.019	2
2-AMINOBENZOYL-ARFK-2,4-DINITROPHENYL ESTER	0.0687	1

Catalyzed reactions (Rhea), 4 shown:

• substance P + H2O = substance P(1-9) + L-Leu-L-Met-NH2 (RHEA:71459)
• substance P + H2O = substance P(1-7) + L-Phe-Gly-L-Leu-L-Met-NH2 (RHEA:71467)
• neurotensin + H2O = neurotensin(1-11) + L-isoleucyl-L-leucine (RHEA:71475)
• neurotensin + H2O = neurotensin(1-10) + L-tyrosyl-L-isoleucyl-L-leucine (RHEA:71479)

UniProt features (105 total): helix 42, strand 15, sequence variant 8, turn 8, disulfide bond 6, binding site 4, glycosylation site 4, sequence conflict 4, active site 2, modified residue 2, topological domain 2, initiator methionine 1, chain 1, lipid moiety-binding region 1, transmembrane region 1, domain 1, region of interest 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
6SUK	X-RAY DIFFRACTION	1.75
6GID	X-RAY DIFFRACTION	1.9
1R1H	X-RAY DIFFRACTION	1.95
5JMY	X-RAY DIFFRACTION	2
2QPJ	X-RAY DIFFRACTION	2.05
1DMT	X-RAY DIFFRACTION	2.1
6SH1	X-RAY DIFFRACTION	2.1
4CTH	X-RAY DIFFRACTION	2.15
1Y8J	X-RAY DIFFRACTION	2.25
1R1J	X-RAY DIFFRACTION	2.35
2YB9	X-RAY DIFFRACTION	2.4
6THP	X-RAY DIFFRACTION	2.54
1R1I	X-RAY DIFFRACTION	2.6
6SH2	X-RAY DIFFRACTION	2.6
6SVY	X-RAY DIFFRACTION	2.6
6XVP	X-RAY DIFFRACTION	2.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08473-F1	96.25	0.94

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 (2): 651 (proton donor); 585

Ligand- & substrate-binding residues (4): 103; 584; 588; 647

Post-translational modifications (3): 4, 6, 2

Disulfide bonds (6): 57–62, 80–735, 88–695, 143–411, 234–242, 621–747

Glycosylation sites (4): 145, 285, 325, 628

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-2022377	Metabolism of Angiotensinogen to Angiotensins
R-HSA-5578768	Physiological factors
R-HSA-6798695	Neutrophil degranulation
R-HSA-9927432	Developmental Lineage of Mammary Gland Myoepithelial Cells
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-2980736	Peptide hormone metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction

MSigDB gene sets: 423 (showing top): GOBP_MEMORY, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_COGNITION, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE, MODULE_169, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, CHIARETTI_T_ALL_REFRACTORY_TO_THERAPY, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS

GO Biological Process (29): kidney development (GO:0001822), placenta development (GO:0001890), angiotensin maturation (GO:0002003), proteolysis (GO:0006508), peptide metabolic process (GO:0006518), learning or memory (GO:0007611), memory (GO:0007613), substance P catabolic process (GO:0010814), bradykinin catabolic process (GO:0010815), protein processing (GO:0016485), sensory perception of pain (GO:0019233), amygdala development (GO:0021764), hippocampus development (GO:0021766), protein catabolic process (GO:0030163), lung development (GO:0030324), multicellular organism growth (GO:0035264), hormone catabolic process (GO:0042447), response to estrogen (GO:0043627), creatinine metabolic process (GO:0046449), amyloid-beta metabolic process (GO:0050435), positive regulation of neurogenesis (GO:0050769), neuropeptide processing (GO:0061837), cellular response to cytokine stimulus (GO:0071345), cellular response to UV-A (GO:0071492), cellular response to UV-B (GO:0071493), replicative senescence (GO:0090399), amyloid-beta clearance (GO:0097242), amyloid-beta clearance by cellular catabolic process (GO:0150094), positive regulation of long-term synaptic potentiation (GO:1900273)

GO Molecular Function (15): phosphatidylserine binding (GO:0001786), endopeptidase activity (GO:0004175), metallocarboxypeptidase activity (GO:0004181), metalloendopeptidase activity (GO:0004222), exopeptidase activity (GO:0008238), zinc ion binding (GO:0008270), peptide binding (GO:0042277), protein homodimerization activity (GO:0042803), oligopeptidase activity (GO:0070012), cardiolipin binding (GO:1901612), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (24): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), early endosome (GO:0005769), trans-Golgi network (GO:0005802), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), brush border (GO:0005903), focal adhesion (GO:0005925), synaptic vesicle (GO:0008021), cell surface (GO:0009986), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), secretory granule membrane (GO:0030667), cytoplasmic vesicle (GO:0031410), ciliary basal body (GO:0036064), neuronal cell body (GO:0043025), neuron projection terminus (GO:0044306), membrane raft (GO:0045121), synapse (GO:0045202), extracellular exosome (GO:0070062), presynapse (GO:0098793), extracellular region (GO:0005576)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Peptide hormone metabolism	1
Cardiac conduction	1
Innate Immune System	1
Developmental Lineages of the Mammary Gland	1
Immune System	1
Metabolism of proteins	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
animal organ development	3
peptidase activity	3
neuron projection	3
protein metabolic process	2
metabolic process	2
catabolic process	2
limbic system development	2
anatomical structure development	2
endopeptidase activity	2
binding	2
microtubule organizing center	2
cytoplasm	2
renal system development	1
regulation of angiotensin levels in blood	1
peptide hormone processing	1
behavior	1
cognition	1
learning or memory	1
neuropeptide catabolic process	1
proteolysis	1
protein maturation	1
sensory perception	1
pallium development	1
macromolecule catabolic process	1
respiratory tube development	1
respiratory system development	1
multicellular organismal process	1
developmental growth	1
hormone metabolic process	1
response to hormone	1
lactam metabolic process	1
phospholipid binding	1
anion binding	1
modified amino acid binding	1
carboxypeptidase activity	1
metalloexopeptidase activity	1
metallopeptidase activity	1
transition metal ion binding	1
identical protein binding	1

Protein interactions and networks

STRING

2460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MME	CD19	P15391	954
MME	IDE	P14735	941
MME	CD5	P06127	925
MME	BCL6	P41182	921
MME	ANPEP	P15144	893
MME	ACE	P12821	883
MME	CD79A	P11912	870
MME	NCAM1	P13591	858
MME	APP	P05067	849
MME	PAX5	Q02548	843
MME	CD34	P28906	842
MME	CD22	P20273	841
MME	CD7	P09564	840
MME	FUT4	P22083	824
MME	CD38	P28907	821

IntAct

26 interactions, top by confidence:

A	B	Type	Score
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
FMR1	MME	psi-mi:“MI:0915”(physical association)	0.560
APP	MME	psi-mi:“MI:0915”(physical association)	0.560
HSPB1	MME	psi-mi:“MI:0915”(physical association)	0.540
HSPB1	MME	psi-mi:“MI:0403”(colocalization)	0.540
MME	HSPB1	psi-mi:“MI:0914”(association)	0.540
MME	TMEM223	psi-mi:“MI:0914”(association)	0.530
MME	HSPA1A	psi-mi:“MI:0915”(physical association)	0.500
CD9	MME	psi-mi:“MI:0915”(physical association)	0.500
MME	CD9	psi-mi:“MI:0915”(physical association)	0.500
NDRG1	MME	psi-mi:“MI:0915”(physical association)	0.400
ACTB	DDX3X	psi-mi:“MI:0915”(physical association)	0.400
SNRK	MME	psi-mi:“MI:0915”(physical association)	0.400
MME		psi-mi:“MI:0914”(association)	0.350
CD177	MYO1G	psi-mi:“MI:0914”(association)	0.350
TEX101	GGT3P	psi-mi:“MI:0914”(association)	0.350
HDAC8	SEC16A	psi-mi:“MI:0914”(association)	0.350
MME	HLA-A	psi-mi:“MI:0914”(association)	0.350

BioGRID (162): GLT8D2 (Affinity Capture-MS), LEMD3 (Affinity Capture-MS), PXMP2 (Affinity Capture-MS), POMGNT1 (Affinity Capture-MS), SLC10A7 (Affinity Capture-MS), STARD3 (Affinity Capture-MS), MANEAL (Affinity Capture-MS), TENM3 (Affinity Capture-MS), TMEM223 (Affinity Capture-MS), ACSL4 (Affinity Capture-MS), B4GALT1 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), SLC22A18 (Affinity Capture-MS), PLD6 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4K692, A5HUI5, B2RQR8, D3UW23, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD9, P15144, P15145, P15684, P16406, P42891, P42892, P42893, P50123, P97739, Q07075, Q10715, Q10751, Q18673, Q22523, Q32LQ0, Q495T6, Q4PZA2, Q56H28, Q56NL1, Q58DD0, Q5EGZ1, Q5RE69, Q5RFN1, Q61391, Q6Q4G4, Q8IS64

Diamond homologs: A0A0B4K692, B2RQR8, F1N476, O16796, O44857, O95672, P07861, P08049, P08473, P0C1T0, P0DPD6, P0DPD8, P0DPD9, P0DPE2, P42891, P42892, P42893, P70669, P78562, P97739, Q18673, Q22523, Q495T6, Q4PZA2, Q5RE69, Q61391, Q8IS64, Q8T062, Q9JHL3, Q9JLI3, Q9JMI0, Q9W436, Q9W5Y0, W4VS99, P23276, Q9EQF2, P19621, A5PK19, A5WVX1, P0DPD7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CSNK2A1	down-regulates	MME	phosphorylation
CSNK2B	unknown	MME	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	59
Likely pathogenic	36
Uncertain significance	337
Likely benign	258
Benign	60

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1326924	NM_007289.4(MME):c.716_717del (p.Lys239fs)	Pathogenic
1352800	NM_007289.4(MME):c.792del (p.Ile264fs)	Pathogenic
1358707	NM_007289.4(MME):c.1153C>T (p.Arg385Ter)	Pathogenic
1382696	NM_007289.4(MME):c.264C>A (p.Cys88Ter)	Pathogenic
1386074	NM_007289.4(MME):c.612_615del (p.Phe204fs)	Pathogenic
1423022	NM_007289.4(MME):c.1502_1503insTG (p.Tyr502fs)	Pathogenic
1424319	NM_007289.4(MME):c.929del (p.Asn310fs)	Pathogenic
1451159	NM_007289.4(MME):c.298del (p.Thr100fs)	Pathogenic
1452456	NM_007289.4(MME):c.900_901dup (p.Asn301fs)	Pathogenic
1453652	NM_007289.4(MME):c.1689dup (p.Phe564fs)	Pathogenic
1455300	NM_007289.4(MME):c.604_607del (p.Asn202fs)	Pathogenic
1455495	NM_007289.4(MME):c.1238del (p.Asn413fs)	Pathogenic
1456285	NC_000003.11:g.(?154832763)(154836620_?)del	Pathogenic
1458704	NC_000003.11:g.(?154801957)(154802903_?)del	Pathogenic
1459271	NM_007289.4(MME):c.1815del (p.Trp606fs)	Pathogenic
1904791	NM_007289.4(MME):c.1818G>A (p.Trp606Ter)	Pathogenic
2094322	NM_007289.4(MME):c.121_125delinsCTATGA (p.Ile41_Ala42delinsLeuTer)	Pathogenic
2102243	NM_007289.4(MME):c.572del (p.Leu191fs)	Pathogenic
2425709	NC_000003.11:g.(?154801957)(154898248_?)del	Pathogenic
242837	NM_007289.4(MME):c.654+1G>A	Pathogenic
242838	NM_007289.4(MME):c.661C>T (p.Gln221Ter)	Pathogenic
242840	NM_007289.4(MME):c.439+2T>A	Pathogenic
242841	NM_007289.4(MME):c.655-2A>G	Pathogenic
253194	NM_007289.4(MME):c.428G>A (p.Cys143Tyr)	Pathogenic
2581575	NM_007289.4(MME):c.1119_1127del (p.Trp373_Ile376delinsTer)	Pathogenic
265743	NM_007289.4(MME):c.71G>A (p.Trp24Ter)	Pathogenic
2695515	NM_007289.4(MME):c.1718T>A (p.Leu573Ter)	Pathogenic
2751588	NM_007289.4(MME):c.19dup (p.Gln7fs)	Pathogenic
2759674	NM_007289.4(MME):c.1066A>T (p.Lys356Ter)	Pathogenic
2766250	NM_007289.4(MME):c.1887_1888del (p.Ser630fs)	Pathogenic

SpliceAI

3713 predictions. Top by Δscore:

Variant	Effect	Δscore
3:155024320:TGGCT:T	donor_gain	1.0000
3:155024321:GGCT:G	donor_gain	1.0000
3:155024321:GGCTG:G	donor_gain	1.0000
3:155024322:GCT:G	donor_gain	1.0000
3:155024322:GCTG:G	donor_gain	1.0000
3:155024323:CT:C	donor_gain	1.0000
3:155024325:G:GG	donor_gain	1.0000
3:155024333:T:G	donor_gain	1.0000
3:155084156:A:AG	acceptor_gain	1.0000
3:155084157:G:GT	acceptor_gain	1.0000
3:155084157:GA:G	acceptor_gain	1.0000
3:155084157:GATT:G	acceptor_gain	1.0000
3:155084157:GATTT:G	acceptor_gain	1.0000
3:155084324:GATG:G	donor_gain	1.0000
3:155084325:ATG:A	donor_gain	1.0000
3:155084325:ATGG:A	donor_loss	1.0000
3:155084326:TG:T	donor_gain	1.0000
3:155084326:TGGTG:T	donor_loss	1.0000
3:155084327:GG:G	donor_gain	1.0000
3:155084327:GGTG:G	donor_loss	1.0000
3:155084328:G:GA	donor_loss	1.0000
3:155084328:G:GG	donor_gain	1.0000
3:155084329:T:A	donor_loss	1.0000
3:155085056:TAG:T	acceptor_loss	1.0000
3:155085057:A:AG	acceptor_gain	1.0000
3:155085057:A:T	acceptor_loss	1.0000
3:155085057:AGAT:A	acceptor_gain	1.0000
3:155085057:AGATG:A	acceptor_gain	1.0000
3:155085058:G:GG	acceptor_gain	1.0000
3:155085058:GA:G	acceptor_gain	1.0000

AlphaMissense

4995 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:155144419:T:A	W460R	1.000
3:155144419:T:C	W460R	1.000
3:155144421:G:C	W460C	1.000
3:155144421:G:T	W460C	1.000
3:155166992:A:C	H584P	1.000
3:155166995:A:T	E585V	1.000
3:155166996:A:C	E585D	1.000
3:155166996:A:T	E585D	1.000
3:155167003:C:G	H588D	1.000
3:155115060:G:A	C88Y	0.999
3:155143478:G:C	W408C	0.999
3:155143478:G:T	W408C	0.999
3:155143485:T:C	C411R	0.999
3:155144446:G:C	A469P	0.999
3:155144457:G:C	K472N	0.999
3:155144457:G:T	K472N	0.999
3:155160391:T:A	W535R	0.999
3:155160391:T:C	W535R	0.999
3:155160393:G:C	W535C	0.999
3:155160393:G:T	W535C	0.999
3:155160421:T:C	F545L	0.999
3:155160423:T:A	F545L	0.999
3:155160423:T:G	F545L	0.999
3:155166911:C:A	A557D	0.999
3:155166920:T:C	L560P	0.999
3:155166977:G:A	G579D	0.999
3:155166989:G:A	G583E	0.999
3:155166991:C:A	H584N	0.999
3:155166991:C:G	H584D	0.999
3:155166992:A:T	H584L	0.999

dbSNP variants (sampled 300 via entrez): RS1000030028 (3:155061406 G>C), RS1000062607 (3:155109197 G>A), RS1000092376 (3:155139301 C>T), RS1000104402 (3:155177364 G>T), RS1000106615 (3:155045191 G>A,T), RS1000117054 (3:155158450 C>T), RS1000122603 (3:155055335 T>A), RS1000126238 (3:155085733 A>G), RS1000132482 (3:155139412 A>T), RS1000134347 (3:155116015 ACAATT>A), RS1000163386 (3:155137904 C>T), RS1000177503 (3:155164759 T>C), RS1000209124 (3:155183379 G>T), RS1000252173 (3:155178251 C>A), RS1000310380 (3:155114581 C>A,G)

Disease associations

OMIM: gene MIM:120520 | disease phenotypes: MIM:617018, MIM:160500, MIM:118220, MIM:617017

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease axonal type 2T	Definitive	Semidominant
spinocerebellar ataxia 43	Supportive	Autosomal dominant
Charcot-Marie-Tooth disease type 2T	Supportive	Autosomal recessive
MME-related autosomal dominant Charcot Marie Tooth disease type 2	Supportive	Autosomal dominant
congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease axonal type 2T	Definitive	AR

Mondo (10): spinocerebellar ataxia 43 (MONDO:0014867), (MONDO:0014866), peripheral neuropathy (MONDO:0005244), distal myopathy (MONDO:0018949), MME-related autosomal dominant Charcot Marie Tooth disease type 2 (MONDO:0044657), Charcot-Marie-Tooth disease (MONDO:0015626), Charcot-Marie-Tooth disease type 2 (MONDO:0018993), Charcot-Marie-Tooth disease type 2T (MONDO:0044640), congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization (MONDO:0019068), hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (10): Spinocerebellar ataxia type 43 (Orphanet:497764), DNAJB2-related Charcot-Marie-Tooth disease type 2 (Orphanet:443950), Distal myopathy (Orphanet:599), MME-related autosomal dominant Charcot Marie Tooth disease type 2 (Orphanet:497757), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Autosomal dominant Charcot-Marie-Tooth disease type 2 (Orphanet:64746), Charcot-Marie-Tooth disease type 2T (Orphanet:495274), Congenital membranous nephropathy due to fetomaternal anti-neutral endopeptidase alloimmunization (Orphanet:69063), Autosomal recessive axonal hereditary motor and sensory neuropathy (Orphanet:91024), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000099	Glomerulonephritis
HP:0000100	Nephrotic syndrome
HP:0000571	Hypometric saccades
HP:0000639	Nystagmus
HP:0000726	Dementia
HP:0000768	Pectus carinatum
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001337	Tremor
HP:0001761	Pes cavus
HP:0002063	Rigidity
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002172	Postural instability
HP:0002317	Unsteady gait
HP:0002396	Cogwheel rigidity
HP:0002936	Distal sensory impairment
HP:0003387	Decreased number of large peripheral myelinated nerve fibers
HP:0003477	Peripheral axonal neuropathy
HP:0003584	Late onset
HP:0003596	Middle age onset
HP:0003677	Slowly progressive
HP:0003693	Distal amyotrophy
HP:0006855	Cerebellar vermis atrophy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004030_30	Primary sclerosing cholangitis	3.000000e-06
GCST007094_142	Diastolic blood pressure	3.000000e-13
GCST007099_22	Systolic blood pressure	4.000000e-12
GCST011385_1	Vaginal microbiome composition (Shannon diversity index)	4.000000e-06
GCST011742_14	Triglyceride levels in HIV infection	7.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0011013	vaginal microbiome measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1944 (SINGLE PROTEIN), CHEMBL6066554 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 5,783 (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
CHEMBL17205	CYCLOVALONE	2	348
CHEMBL289556	OMAPATRILAT	2	799
CHEMBL42583	SAMPATRILAT	2	3,529
CHEMBL434492	CANDOXATRILAT	2	1,107

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2016848	Toxicity	3	Ace Inhibitors;Plain	Cough;Hypertension

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2016848	MME	3	2.50	1	Ace Inhibitors;Plain
rs989692	MME		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — M13: Neprilysin

Most potent curated ligand interactions (9 total), top 9:

Ligand	Action	Affinity	Parameter
compound 1b [PMID: 18078750]	Inhibition	8.89	pKi
compound 1a [PMID: 25692029]	Inhibition	8.85	pKi
kelatorphan	Inhibition	8.77	pKi
phosphoramidon	Inhibition	8.4	pKi
KC-12615	Inhibition	8.4	pIC50
fasidotrilat	Inhibition	8.3	pKi
sacubitrilat	Inhibition	8.14	pIC50
AD015	Inhibition	8.05	pIC50
candoxatrilat	Inhibition	7.6	pIC50

Binding affinities (BindingDB)

159 measured of 342 human assays (342 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-[[(2S,4R)-4-carboxy-1-[4-(3-chlorophenyl)phenyl]pentan-2-yl]carbamoyl]-1H-pyrazole-5-carboxylic acid	IC50	0.03 nM	US-9006249: Substituted aminobutyric derivatives as neprilysin inhibitors
(2R,4S)-4-[[(Z)-4-amino-2-hydroxy-4-oxobut-2-enoyl]amino]-5-[4-(3-chlorophenyl)phenyl]-2-methylpentanoic acid	IC50	0.04 nM	US-9603819: Substituted aminobutyric derivatives as neprilysin inhibitors
ethyl (2S)-2-[[(2S)-3-[4-(3-chlorophenyl)phenyl]-1-oxo-1-(2H-tetrazol-5-ylamino)propan-2-yl]amino]propanoate	IC50	0.09 nM	US-8877786: Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
(3R)-4-[4-(5-chloro-2-fluorophenyl)phenyl]-3-(3-phosphonopropanoylamino)butanoic acid	IC50	0.11 nM	US-9163040: Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
(2S)-2-[[(2S)-3-[4-(3-chlorophenyl)phenyl]-1-(2,3-dihydro-1H-tetrazol-5-ylamino)-1-oxopropan-2-yl]amino]-4-phenylbutanoic acid	IC50	0.2 nM	US-8877786: Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
(2S)-2-[[(2S)-3-[4-(3-chlorophenyl)phenyl]-1-(2,3-dihydro-1H-tetrazol-5-ylamino)-1-oxopropan-2-yl]amino]butanoic acid	IC50	0.2 nM	US-8877786: Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
tert-butyl (2S)-2-[[(2S)-3-[4-(2,5-dichlorophenyl)phenyl]-1-oxo-1-(2H-tetrazol-5-ylamino)propan-2-yl]amino]propanoate	IC50	0.3 nM	US-8877786: Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
(2S,4S)-5-[4-(3-chlorophenyl)phenyl]-2-methyl-4-[(3-oxo-1,2-oxazole-5-carbonyl)amino]pentanoic acid	IC50	0.3 nM	US-8993631: Method of treating contrast-induced nephropathy
5-[[(2S,4R)-4-carboxy-1-[4-(3-chlorophenyl)phenyl]pentan-2-yl]carbamoyl]furan-2-carboxylic acid	IC50	0.3 nM	US-9006249: Substituted aminobutyric derivatives as neprilysin inhibitors
6-[[(2S,4R)-4-carboxy-1-(4-phenylphenyl)pentan-2-yl]carbamoyl]pyrimidine-4-carboxylic acid	IC50	1 nM	US-8993631: Method of treating contrast-induced nephropathy
US9593110, Example 54	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-2-(2H-tetrazol-5-ylmethyl)-4-(2H-triazole-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4R)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-2-[[2-(dimethylamino)acetyl]amino]-4-(2H-triazole-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4R)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-2-[[2-(methylamino)acetyl]amino]-4-(2H-triazole-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
ethyl (2S,4S)-2-[(2E)-2-amino-2-hydroxyiminoethyl]-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-(2H-triazole-4-carbonylamino)pentanoate	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 69a	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 74	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 75	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 22	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 23	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 78	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 79	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-2-(2-hydroxyethoxymethyl)-5-(4-phenylphenyl)-4-(2H-triazole-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-2-(3-hydroxypropoxymethyl)-5-(4-phenylphenyl)-4-(2H-triazole-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 36-1	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 36-2	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4R)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-[(4-propan-2-yl-1,3-oxazole-2-carbonyl)amino]pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 42-1	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 42-2	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4R)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-2-[[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]amino]-4-(triazolidine-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 101c	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 48b	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-2-(cyanomethyl)-4-(2H-triazole-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
US9593110, Example 106	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-[(5-cyclopropyl-4-fluoro-1H-pyrazole-3-carbonyl)amino]-2-(methoxymethyl)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4R)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-2-[[(2S)-2,6-diaminohexanoyl]amino]-4-(2H-triazole-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4R)-2-amino-5-[2-chloro-4-(5-chloro-2-fluorophenyl)phenyl]-4-[(3-ethyl-1,2-oxazole-5-carbonyl)amino]pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-2-(methoxymethyl)-4-[(2-oxo-3H-1,3-oxazole-5-carbonyl)amino]pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-2-(aminomethyl)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-[(2-cyclopropyl-1,3-oxazole-4-carbonyl)amino]pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-2-(aminomethyl)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-[(2-ethoxy-1,3-oxazole-4-carbonyl)amino]pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-2-(aminomethyl)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-[(2-methyl-1,3-oxazole-4-carbonyl)amino]pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-2-(aminomethyl)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-[(3-methyl-1,2-thiazole-5-carbonyl)amino]pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-2-(aminomethyl)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-(1,2-thiazole-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-2-(ethoxymethyl)-4-(1,3-oxazole-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2S,4S)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-[(2-cyclopropyl-1,3-oxazole-4-carbonyl)amino]-2-(ethoxymethyl)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4S)-2-(2-aminoethyl)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-(2H-triazole-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4R)-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-[(5-ethoxy-4-methyl-1,3-oxazole-2-carbonyl)amino]-2-(methoxycarbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4R)-2-amino-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-[(3-ethyl-1,2-oxazole-5-carbonyl)amino]pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4R)-2-amino-5-[4-(5-chloro-2-fluorophenyl)phenyl]-4-[(5-propyl-1,2-oxazole-3-carbonyl)amino]pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors
(2R,4R)-2-(methoxycarbonylamino)-5-(4-phenylphenyl)-4-(triazolidine-4-carbonylamino)pentanoic acid	KI	2.2 nM	US-9593110: Neprilysin inhibitors

ChEMBL bioactivities

832 potent at pChembl≥5 of 874 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.52	IC50	0.03	nM	CHEMBL3677673
10.40	IC50	0.04	nM	CHEMBL3677671
10.40	IC50	0.04	nM	CHEMBL5971490
10.10	IC50	0.08	nM	CHEMBL198316
10.05	IC50	0.09	nM	CHEMBL3695448
9.96	IC50	0.11	nM	CHEMBL3890914
9.70	IC50	0.2	nM	CHEMBL3695453
9.70	IC50	0.2	nM	CHEMBL3695454
9.70	IC50	0.1995	nM	OMAPATRILAT
9.70	Ki	0.2	nM	CHEMBL5931110
9.55	Ki	0.28	nM	CHEMBL271225
9.52	IC50	0.3	nM	CHEMBL3695449
9.52	IC50	0.3	nM	CHEMBL3677674
9.52	IC50	0.3	nM	CHEMBL3703484
9.52	IC50	0.3	nM	CHEMBL1778532
9.52	IC50	0.3	nM	CHEMBL1778534
9.50	Ki	0.316	nM	CHEMBL5848092
9.44	IC50	0.36	nM	CHEMBL1829584
9.42	IC50	0.38	nM	CHEMBL3676144
9.40	Ki	0.4	nM	CHEMBL5272269
9.35	Ki	0.45	nM	OMAPATRILAT
9.30	Ki	0.501	nM	CHEMBL5872996
9.29	IC50	0.51	nM	CHEMBL1829585
9.22	IC50	0.6	nM	CHEMBL51389
9.22	IC50	0.6	nM	CHEMBL268473
9.22	IC50	0.6	nM	SAMPATRILAT
9.22	IC50	0.6	nM	CHEMBL1778530
9.20	IC50	0.631	nM	CHEMBL4443691
9.20	IC50	0.631	nM	CHEMBL4435800
9.20	Ki	0.631	nM	CHEMBL5842509
9.19	Ki	0.64	nM	CYCLOVALONE
9.16	IC50	0.69	nM	CHEMBL34541
9.15	Ki	0.7	nM	CHEMBL51715
9.15	IC50	0.7	nM	CHEMBL276690
9.15	Ki	0.7	nM	CHEMBL2052008
9.13	IC50	0.74	nM	CHEMBL276872
9.10	IC50	0.8	nM	CHEMBL2204326
9.10	IC50	0.8	nM	CHEMBL4443138
9.10	Ki	0.8	nM	CHEMBL257726
9.05	IC50	0.9	nM	CHEMBL150222
9.05	IC50	0.9	nM	CHEMBL290698
9.00	IC50	1	nM	CHEMBL290698
9.00	IC50	1	nM	THIORPHAN
9.00	IC50	1	nM	CHEMBL3677663
9.00	IC50	1	nM	CHEMBL51780
9.00	IC50	1	nM	CHEMBL4469350
9.00	IC50	1	nM	CHEMBL4547120
9.00	IC50	1	nM	CHEMBL4456519
9.00	IC50	1	nM	CHEMBL4465325
9.00	Ki	1	nM	CHEMBL5750525

PubChem BioAssay actives

383 with measured affinity, of 648 total; 50 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
(4R,7S)-6-oxo-7-[[(2R)-3-phenyl-2-sulfanylpropanoyl]amino]-2,3,4,7,8,12b-hexahydro-1H-pyrido[2,1-a][2]benzazepine-4-carboxylic acid	254702: Inhibitory concentration against neutral endopeptidase	ic50	0.0001	uM
(4S,7S,10aS)-5-oxo-4-[[(2S)-3-phenyl-2-sulfanylpropanoyl]amino]-2,3,4,7,8,9,10,10a-octahydropyrido[2,1-b][1,3]thiazepine-7-carboxylic acid	1515581: Inhibition of NEP (unknown origin) preincubated for 10 mins followed by fluorogenic substrate addition and measured after 20 mins by fluorescence assay	ic50	0.0002	uM
(2S)-2-[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]-3-(4-phenylphenyl)propanoic acid	317220: Inhibition of human recombinant NEP by fluorescence assay	ki	0.0003	uM
(2S)-2-[[1-[[(1S)-1-carboxy-2-(5-phenyl-1,3-oxazol-2-yl)ethyl]carbamoyl]cyclopentyl]amino]-4-methoxybutanoic acid	598052: Inhibition of neutral endopeptidase	ic50	0.0003	uM
(2S)-2-[[1-[[(1S)-1-carboxy-2-[5-(4-chlorophenyl)-1,3-oxazol-2-yl]ethyl]carbamoyl]cyclopentyl]amino]-4-methoxybutanoic acid	598052: Inhibition of neutral endopeptidase	ic50	0.0003	uM
(2R,4S)-4-(3-carboxypropanoylamino)-5-[4-(3-chlorophenyl)phenyl]-2-methylpentanoic acid	1542143: Inhibition of recombinant human NEP expressed in insect cells preincubated for 1 hr using Cys(PT14)-Arg-Arg-Leu-Trp-OH as substrate and measured after 1 hr by fluorescence based assay	ic50	0.0003	uM
(2S)-2-[[(2S)-1-(2-carboxyethylamino)-1-oxo-3-(4-phenylphenyl)propan-2-yl]amino]-4-phenylbutanoic acid	620439: Inhibition of neutral endopeptidase in human fibroblasts homogenates using glutaryl-Ala-Ala-Phe-4-methoxy-2-naphtylamide as substrate after 1 hrs by fluorimetric assay	ic50	0.0004	uM
4-[[(2R)-1-carboxy-3-[4-(5-chloro-2-methoxyphenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid	1542143: Inhibition of recombinant human NEP expressed in insect cells preincubated for 1 hr using Cys(PT14)-Arg-Arg-Leu-Trp-OH as substrate and measured after 1 hr by fluorescence based assay	ic50	0.0004	uM
(2S)-4-methyl-2-[(4S)-3-oxo-4-[[(2S)-3-phenyl-2-sulfanylpropanoyl]amino]-4,5-dihydro-1H-2-benzazepin-2-yl]pentanoic acid	1954029: Binding affinity to neutral endopeptidase (unknown origin) assessed as inhibition constant	ki	0.0004	uM
(2S)-2-[[(2S)-1-[[(2S)-2-carboxypropyl]amino]-1-oxo-3-(4-phenylphenyl)propan-2-yl]amino]-4-phenylbutanoic acid	620439: Inhibition of neutral endopeptidase in human fibroblasts homogenates using glutaryl-Ala-Ala-Phe-4-methoxy-2-naphtylamide as substrate after 1 hrs by fluorimetric assay	ic50	0.0005	uM
2-[4-[[2-butyl-4-methyl-5-[[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]methyl]imidazol-1-yl]methyl]phenyl]benzoic acid	1515581: Inhibition of NEP (unknown origin) preincubated for 10 mins followed by fluorogenic substrate addition and measured after 20 mins by fluorescence assay	ic50	0.0006	uM
2-[4-[[2-ethoxy-4-ethyl-5-[[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]methyl]imidazol-1-yl]methyl]-3-fluorophenyl]benzoic acid	1515581: Inhibition of NEP (unknown origin) preincubated for 10 mins followed by fluorogenic substrate addition and measured after 20 mins by fluorescence assay	ic50	0.0006	uM
(2S)-2-[[1-[[(1S)-1-carboxy-2-(5-phenyl-1,3-oxazol-2-yl)ethyl]carbamoyl]cyclopentyl]amino]pentanoic acid	598052: Inhibition of neutral endopeptidase	ic50	0.0006	uM
(2S)-2-[[[(2S)-6-amino-2-(methanesulfonamido)hexanoyl]amino]methyl]-3-[1-[[(1S)-1-carboxy-2-(4-hydroxyphenyl)ethyl]carbamoyl]cyclopentyl]propanoic acid	598052: Inhibition of neutral endopeptidase	ic50	0.0006	uM
(2S)-2-[[(2R,3R)-3-phenyl-2-(sulfanylmethyl)butanoyl]amino]propanoic acid	147206: In vivo inhibitory potency against neutral endopeptidase by displacement of [3H]HACBOGly binding in mouse kidney	ki	0.0007	uM
(2S)-2-[[(2S)-2-benzyl-3-sulfanylpropanoyl]amino]propanoic acid	1224570: Inhibition of human recombinant NEP using Suc-Ala-Ala-Phe-AMC as substrate after 30 mins by fluorimetry	ki	0.0007	uM
(4S)-4-(3-carboxypropanoylamino)-5-[4-(3-chlorophenyl)phenyl]-2-methylpentanoic acid	1542143: Inhibition of recombinant human NEP expressed in insect cells preincubated for 1 hr using Cys(PT14)-Arg-Arg-Leu-Trp-OH as substrate and measured after 1 hr by fluorescence based assay	ic50	0.0008	uM
(2S)-3-(4-phenylphenyl)-2-[[(2S)-2-sulfanylbutanoyl]amino]propanoic acid	317220: Inhibition of human recombinant NEP by fluorescence assay	ki	0.0008	uM
(2S,4R)-4-hydroxy-1-[(2S,9R)-10-oxo-9-(sulfanylmethyl)azecane-2-carbonyl]pyrrolidine-2-carboxylic acid	711507: Inhibition of neutral endopeptidase	ic50	0.0008	uM
(3S,6S)-4-oxo-3-(sulfanylmethyl)-5-azabicyclo[9.4.0]pentadeca-1(15),11,13-triene-6-carboxylic acid	147391: Inhibition of neutral endopeptidase	ic50	0.0009	uM
[[(1S)-2-(4-phenylphenyl)-1-(2H-tetrazol-5-yl)ethyl]amino]methylphosphonic acid	147365: Inhibitory activity against neutral endopeptidase (NEP).	ic50	0.0010	uM
2-[4-[[2-butyl-4-chloro-5-[[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]methyl]imidazol-1-yl]methyl]phenyl]benzoic acid	1515581: Inhibition of NEP (unknown origin) preincubated for 10 mins followed by fluorogenic substrate addition and measured after 20 mins by fluorescence assay	ic50	0.0010	uM
2-[4-[[2-butyl-4-cyclopropyl-5-[[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]methyl]imidazol-1-yl]methyl]phenyl]benzoic acid	1515581: Inhibition of NEP (unknown origin) preincubated for 10 mins followed by fluorogenic substrate addition and measured after 20 mins by fluorescence assay	ic50	0.0010	uM
2-[(2-benzyl-3-sulfanylpropanoyl)amino]acetic acid	1127282: Inhibition of human NEP-mediated amyloid beta hydrolysis	ic50	0.0010	uM
2-[4-[[4-ethyl-5-[[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]methyl]-2-propoxyimidazol-1-yl]methyl]phenyl]benzoic acid	1515581: Inhibition of NEP (unknown origin) preincubated for 10 mins followed by fluorogenic substrate addition and measured after 20 mins by fluorescence assay	ic50	0.0010	uM
2-[4-[[2-ethoxy-4-ethyl-5-[[[(2S)-4-methyl-2-sulfanylpentanoyl]amino]methyl]imidazol-1-yl]methyl]phenyl]benzoic acid	1515581: Inhibition of NEP (unknown origin) preincubated for 10 mins followed by fluorogenic substrate addition and measured after 20 mins by fluorescence assay	ic50	0.0010	uM
(2S)-3-(4-phenylphenyl)-2-[[(2S)-3-phenyl-2-sulfanylpropanoyl]amino]propanoic acid	317220: Inhibition of human recombinant NEP by fluorescence assay	ki	0.0011	uM
(2S)-2-[[(2R)-2-[[[(1S)-1-aminoethyl]-hydroxyphosphoryl]methyl]-3-(4-phenylphenyl)propanoyl]amino]propanoic acid	147396: Compound was evaluated for inhibition of enkephalin degrading enzyme, neutral endopeptidase (NEP)	ki	0.0012	uM
(2S)-3-(4-phenylphenyl)-2-[[(2S)-2-sulfanylhexanoyl]amino]propanoic acid	317220: Inhibition of human recombinant NEP by fluorescence assay	ki	0.0012	uM
2-[[3-phenyl-2-(sulfanylmethyl)butanoyl]amino]acetic acid	147205: In vivo inhibitory potency against neutral endopeptidase by displacement of [3H]HACBOGly binding in mouse kidney	ic50	0.0013	uM
(2S)-3-(4-phenylphenyl)-2-[[(2R)-3-phenyl-2-sulfanylpropanoyl]amino]propanoic acid	317220: Inhibition of human recombinant NEP by fluorescence assay	ki	0.0013	uM
2-[[2-benzyl-4-(hydroxyamino)-4-oxobutanoyl]amino]acetic acid	147393: Inhibitory potency against neutral endopeptidase	ic50	0.0014	uM
(2S)-2-[[2-benzyl-3-[hydroxy-[(1R)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	444547: Inhibition of human somatic NEP	ki	0.0014	uM
2-[[(2S)-2-benzyl-3-sulfanylpropanoyl]amino]acetic acid	1224570: Inhibition of human recombinant NEP using Suc-Ala-Ala-Phe-AMC as substrate after 30 mins by fluorimetry	ki	0.0015	uM
4-[[(2R)-1-carboxy-3-[4-(3-chlorophenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid	1542143: Inhibition of recombinant human NEP expressed in insect cells preincubated for 1 hr using Cys(PT14)-Arg-Arg-Leu-Trp-OH as substrate and measured after 1 hr by fluorescence based assay	ic50	0.0015	uM
(2S)-2-[[(2S)-2-benzyl-3-sulfanylpropanoyl]amino]butanedioic acid	1224570: Inhibition of human recombinant NEP using Suc-Ala-Ala-Phe-AMC as substrate after 30 mins by fluorimetry	ki	0.0015	uM
4-[[(2R)-1-carboxy-3-[4-(3-methylphenyl)phenyl]propan-2-yl]amino]-4-oxobutanoic acid	1542143: Inhibition of recombinant human NEP expressed in insect cells preincubated for 1 hr using Cys(PT14)-Arg-Arg-Leu-Trp-OH as substrate and measured after 1 hr by fluorescence based assay	ic50	0.0016	uM
(2S)-3-phenyl-2-[[(2R,3R)-3-phenyl-2-(sulfanylmethyl)butanoyl]amino]propanoic acid	147206: In vivo inhibitory potency against neutral endopeptidase by displacement of [3H]HACBOGly binding in mouse kidney	ki	0.0016	uM
(2S)-2-[[(2R)-2-benzyl-4-(hydroxyamino)-4-oxobutanoyl]amino]propanoic acid	147396: Compound was evaluated for inhibition of enkephalin degrading enzyme, neutral endopeptidase (NEP)	ki	0.0017	uM
(2S)-2-[[1-[[(1S)-1-carboxy-2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]carbamoyl]cyclopentyl]amino]-4-methoxybutanoic acid	598052: Inhibition of neutral endopeptidase	ic50	0.0019	uM
(2S)-4-oxo-4-(1-sulfanylcyclohexyl)-2-[(4-thiophen-3-ylphenyl)methyl]butanoic acid	1487444: Inhibition of recombinant human neprilysin using Suc-Ala-Ala-Phe-AMC as substrate preincubated for 30 mins followed by substrate addition measured after 30 mins by fluorescence assay	ki	0.0020	uM
2-[(2-benzyl-3-sulfanylpropanoyl)amino]-3-(4-hydroxyphenyl)propanoic acid	147205: In vivo inhibitory potency against neutral endopeptidase by displacement of [3H]HACBOGly binding in mouse kidney	ic50	0.0020	uM
2-[[3-(4-fluorophenyl)-2-(sulfanylmethyl)butanoyl]amino]propanoic acid	147205: In vivo inhibitory potency against neutral endopeptidase by displacement of [3H]HACBOGly binding in mouse kidney	ic50	0.0020	uM
2-[[3-(1,3-benzodioxol-5-yl)-2-(sulfanylmethyl)butanoyl]amino]propanoic acid	147205: In vivo inhibitory potency against neutral endopeptidase by displacement of [3H]HACBOGly binding in mouse kidney	ic50	0.0020	uM
benzyl 2-[[(2S)-2-[[[(2S)-2-amino-4-methylsulfanylbutyl]disulfanyl]methyl]-3-phenylpropanoyl]amino]-3-phenylpropanoate	147396: Compound was evaluated for inhibition of enkephalin degrading enzyme, neutral endopeptidase (NEP)	ki	0.0020	uM
(2S)-2-[[(2R)-2-[[[(S)-amino(phenyl)methyl]-hydroxyphosphoryl]methyl]-3-(4-phenylphenyl)propanoyl]amino]propanoic acid	147396: Compound was evaluated for inhibition of enkephalin degrading enzyme, neutral endopeptidase (NEP)	ki	0.0020	uM
(2S)-2-[[2-methylpropyl(phosphonomethyl)carbamoyl]amino]-3-naphthalen-2-ylpropanoic acid	320032: Inhibition of NEP	ic50	0.0020	uM
(2S)-2-[[(2S)-2-[[hydroxy-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	620439: Inhibition of neutral endopeptidase in human fibroblasts homogenates using glutaryl-Ala-Ala-Phe-4-methoxy-2-naphtylamide as substrate after 1 hrs by fluorimetric assay	ic50	0.0020	uM
(2S,4S)-4-(3-carboxypropanoylamino)-5-[4-(3-chlorophenyl)phenyl]-2-methylpentanoic acid	1542143: Inhibition of recombinant human NEP expressed in insect cells preincubated for 1 hr using Cys(PT14)-Arg-Arg-Leu-Trp-OH as substrate and measured after 1 hr by fluorescence based assay	ic50	0.0020	uM
(2S)-2-[[2-(sulfanylmethyl)-3-thiophen-3-ylpropanoyl]amino]propanoic acid	1224570: Inhibition of human recombinant NEP using Suc-Ala-Ala-Phe-AMC as substrate after 30 mins by fluorimetry	ki	0.0020	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
sodium arsenite	decreases expression, increases expression	4
Estradiol	affects cotreatment, increases expression, decreases expression	4
Tetrachlorodibenzodioxin	affects expression, decreases expression, affects cotreatment, increases expression	4
bisphenol A	decreases methylation, increases expression, decreases expression	3
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation, affects expression (+1 more)	3
Doxorubicin	decreases expression, affects response to substance	3
Ozone	affects cotreatment, increases expression, increases oxidation, increases abundance, affects expression	3
cobaltous chloride	affects binding, increases reaction, decreases expression	2
methacrylaldehyde	affects cotreatment, increases expression, increases oxidation, increases abundance	2
entinostat	increases expression, affects cotreatment	2
bisphenol S	affects methylation, increases expression	2
Acrolein	increases oxidation, increases abundance, affects cotreatment, increases expression	2
Arsenic	affects expression, increases abundance, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Lead	affects folding, decreases activity, decreases expression	2
Oxygen	decreases expression, increases expression	2
Progesterone	decreases expression, increases expression	2
Tretinoin	increases expression, increases reaction	2
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
LBQ657	affects binding	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment, increases expression	1
sodium arsenate	increases abundance, increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
trichostatin A	increases expression	1
beta-lapachone	decreases expression	1

ChEMBL screening assays

125 unique, capped per target: 110 binding, 15 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1002957	Binding	Inhibition of NEP	Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge. — Bioorg Med Chem
CHEMBL3376486	ADMET	Drug metabolism assessed as NEP 24.11 (unknown origin)-mediated degradation up to 24 hrs by HPLC analysis	Development of novel neurokinin 3 receptor (NK3R) selective agonists with resistance to proteolytic degradation. — J Med Chem

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1XA	Abcam HeLa MME KO	Cancer cell line	Female
CVCL_B7Y9	Abcam Raji MME KO	Cancer cell line	Male
CVCL_B9YZ	Abcam THP-1 MME KO	Cancer cell line	Male
CVCL_D9KG	Ubigene HEK293 MME KO	Transformed cell line	Female
CVCL_SY57	HAP1 MME (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	PHASE3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.