NPC1L1

Summary

NPC1L1 (NPC1 like intracellular cholesterol transporter 1, HGNC:7898) is a protein-coding gene on chromosome 7p13, encoding NPC1-like intracellular cholesterol transporter 1 (Q9UHC9). Plays a major role in cholesterol homeostasis.

The protein encoded by this gene is a multi-pass membrane protein. It contains a conserved N-terminal Niemann-Pick C1 (NPC1) domain and a putative sterol-sensing domain (SSD) which includes a YQRL motif functioning as a plasma membrane to trans-Golgi network transport signal in other proteins. This protein takes up free cholesterol into cells through vesicular endocytosis and plays a critical role in the absorption of intestinal cholesterol. It also has the ability to transport alpha-tocopherol (vitamin E). The drug ezetimibe targets this protein and inhibits the absorption of intestinal cholesterol and alpha-tocopherol. In addition, this protein may play a critical role in regulating lipid metabolism. Polymorphic variations in this gene are associated with plasma total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels and coronary heart disease (CHD) risk. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 29881 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 249 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001101648

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7898
Approved symbol	NPC1L1
Name	NPC1 like intracellular cholesterol transporter 1
Location	7p13
Locus type	gene with protein product
Status	Approved
Aliases	SLC65A2
Ensembl gene	ENSG00000015520
Ensembl biotype	protein_coding
OMIM	608010
Entrez	29881

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000289547, ENST00000381160, ENST00000423141, ENST00000546276, ENST00000865305, ENST00000865306

RefSeq mRNA: 3 — MANE Select: NM_001101648 NM_001101648, NM_001300967, NM_013389

CCDS: CCDS43575, CCDS5491, CCDS75587

Canonical transcript exons

ENST00000381160 — 19 exons

Exon	Start	End
ENSE00000347092	44531755	44531844
ENSE00000347099	44515803	44515965
ENSE00000681310	44516084	44516197
ENSE00000681344	44522052	44522242
ENSE00000681350	44532080	44532217
ENSE00000681355	44533739	44533853
ENSE00000681362	44535840	44535968
ENSE00000681365	44536256	44536428
ENSE00000681367	44536842	44536942
ENSE00000681369	44538817	44540342
ENSE00001039684	44520765	44520820
ENSE00001039727	44517207	44517357
ENSE00001122258	44516703	44516934
ENSE00001122282	44520992	44521118
ENSE00001122287	44521712	44521836
ENSE00001122306	44533431	44533558
ENSE00001305030	44534447	44534629
ENSE00001310115	44512535	44513649
ENSE00003903344	44541206	44541330

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 97.21.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8845 / max 220.1333, expressed in 84 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83883	0.6119	66
83884	0.2727	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	97.21	gold quality
duodenum	UBERON:0002114	93.62	gold quality
right lobe of liver	UBERON:0001114	90.99	gold quality
liver	UBERON:0002107	86.31	gold quality
jejunum	UBERON:0002115	77.91	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.52	gold quality
islet of Langerhans	UBERON:0000006	75.26	gold quality
gall bladder	UBERON:0002110	74.46	gold quality
choroid plexus epithelium	UBERON:0003911	73.84	gold quality
sperm	CL:0000019	73.32	gold quality
male germ cell	CL:0000015	71.45	gold quality
parotid gland	UBERON:0001831	69.50	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	67.09	gold quality
lower esophagus mucosa	UBERON:0035834	64.90	gold quality
cerebellar vermis	UBERON:0004720	64.77	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	61.92	gold quality
muscle layer of sigmoid colon	UBERON:0035805	61.22	gold quality
vena cava	UBERON:0004087	60.46	gold quality
right coronary artery	UBERON:0001625	60.41	gold quality
descending thoracic aorta	UBERON:0002345	60.09	gold quality
popliteal artery	UBERON:0002250	59.76	gold quality
aorta	UBERON:0000947	59.73	gold quality
ascending aorta	UBERON:0001496	59.73	gold quality
thoracic aorta	UBERON:0001515	59.71	gold quality
tibial artery	UBERON:0007610	59.67	gold quality
pons	UBERON:0000988	59.62	gold quality
pancreas	UBERON:0001264	58.35	gold quality
biceps brachii	UBERON:0001507	58.33	gold quality
body of tongue	UBERON:0011876	58.31	gold quality
heart right ventricle	UBERON:0002080	58.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXC1, HNF1A, HNF4A, NR1H3, PPARA, PPARD, PPARGC1A, RXRA, SREBF2

miRNA regulators (miRDB)

29 targeting NPC1L1, 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-499A-5P	99.98	70.79	1323
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1255A	99.74	68.09	744
HSA-MIR-1255B-5P	99.74	68.16	741
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-4727-5P	99.23	67.55	1154
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-4457	98.09	67.12	1274
HSA-MIR-203B-5P	97.24	68.54	543
HSA-MIR-6718-5P	97.24	68.15	553
HSA-MIR-122-5P	97.23	64.92	1024
HSA-MIR-6730-3P	97.03	67.54	889
HSA-MIR-4689	96.97	65.79	1209
HSA-MIR-1587	96.95	64.03	932
HSA-MIR-3918	96.13	64.65	1300
HSA-MIR-4654	95.86	65.72	751

Literature-anchored findings (GeneRIF, showing 40)

• expression is enriched in the small intestine and is in the brush border membrane of enterocytes (PMID:14976318)
• NPC1L1 has a role in lipid transport and in diet-induced hypercholesterolemia (PMID:15671032)
• DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol. (PMID:16297596)
• nonsynonymous variant technique to demonstrate that genetic variation in NPC1L1 contributes to variability in cholesterol absorption and plasma levels of low-density lipoproteins (PMID:16449388)
• Intestinal gene expression is altred in type 2 diabetees. Diabetic patients have more NPC1L1 mRNA than the control subjects. (PMID:16518588)
• NPC1L1 contributes to intestinal cholesterol homeostasis and possibly cooperates with SR-BI to mediate cholesterol absorption in humans (PMID:16829661)
• Small variations in ezetimibe structure or in NPC1L1 amino acid sequence can profoundly influence ezetimibe/NPC1L1 interaction and consequently their anticholesteremisc in vivo activity. (PMID:17005902)
• Increased NPC1L1 and lower ABCG5 abd ABCG8 may lead to increased cholesterol and sitosterol in chylomicron particles in diabetic patients. (PMID:17102949)
• hepatic NPC1L1 may have evolved to protect the body from excessive biliary loss of cholesterol (PMID:17571164)
• human NPC1L1 can functionally substitute for the Caenorhabditis elegans genes ncr-1 and/or ncr-2. (PMID:17662536)
• NPC1L1 2/2 haplotype was associated with variation in LDL-apoB metabolism and its response to statin therapy in centrally obese men, by a mechanism that did not involve changes in VLDL-apoB kinetics, nor cholesterol synthesis or absorption. (PMID:18031309)
• HNF4alpha plays a crucial role in the expression and regulation of human NPC1L1 gene (PMID:18080173)
• bile acids upregulate NPC1L1 mRNA and protein levels (PMID:18373109)
• NPC1L1 mediates alpha-tocopherol transport. (PMID:18403720)
• Cholesterol absorption was greatly reduced in individuals with NPC1L1 sequence variation. (PMID:18413323)
• REVIEW: dietary cholesterol induces endocytosis of NPC1L1 at the cell surface (PMID:18522826)
• cholesterol is internalized into cells with NPC1L1 through clathrin/AP2-mediated endocytosis and ezetimibe inhibits cholesterol absorption by blocking the internalization of NPC1L1 (PMID:18522832)
• the present data show that lycopene absorption is, at least in part, mediated by SR-BI but not by Niemann-Pick disease type C1, in human intestinal cells and mice. (PMID:18641187)
• No common polymorphisms in ABCG8, ABCG5, or NPC1L1 were demonstrated between the 3 top responders and the non-respondersto plant sterol intervention.Yet, 1 non-responsive subject did demonstrate a rare SNP in NPC1L1. (PMID:18641716)
• Expression levels of NPC1L1 were 15- to 30-fold higher in the duodenum compared with the liver at transcript and protein levels, respectively, suggesting preferential action of ezetimibe on intestinal cholesterol absorption in humans. (PMID:18783541)
• Results describe the association between ABCG5/G8 and NPC1L1 genotype single nucleotide polymorphisms with sterol absorption and corresponding plasma concentrations. (PMID:18850127)
• The increased NPC1L1 and ACAT2 mRNA levels in gallstone patients might indicate an upregulated absorption and esterification of cholesterol in the small intestine. (PMID:19071091)
• The -762C allele of NPC1L1 had a higher promoter activity and was associated with a higher serum total cholesterol and LDL-cholesterol level. (PMID:19265861)
• study of the topology of NPC1L1; data indicate that NPC1L1 contains 13 transmembrane helices; the NH2-terminus of NPC1L1 is in the lumen while the COOH-terminus projects to the cytosol (PMID:19325169)
• Polyunsaturated fatty acids down-regulate in vitro expression of the key intestinal cholesterol absorption protein NPC1L1 (PMID:19443194)
• NPC1L1 promoter variants might explain in part the hypercholesterolemic phenotype of some subjects with non-LDL receptor/apolipoprotein B autosomal dominant hypercholesterolemia (PMID:19747803)
• NPC1L1 gene is associated with plasma total and LDL-C levels and coronary heart disease risk. (PMID:19752398)
• The transport activity of NPC1L1 variants between cholesterol and alpha-tocopherol, were compared. (PMID:19823104)
• hepatic NPC1L1 in the liver from Chinese female gallstone patients may be mediated by SREBP2 (PMID:20144195)
• inhibition of NPC1L1 by ezetimibe is effective in non-obese patients with nonalcoholic fatty liver disease (PMID:20222991)
• Single nucleotide polymorphism in NPC1L1 is associated with enhanced cholesterol absorption from the intestine. (PMID:20379057)
• regulation by SREBP2 and HNF1alpha on the NPC1L1 promoter activity (PMID:20460578)
• PPARalpha positively regulates human NPC1L1 transcription via direct binding to a PPRE. Additionally, PGC1alpha stimulates the SREBP2/HNF4alpha- and PPARalpha/RXRalpha- mediated transactivation of human NPC1L1 (PMID:20953676)
• flotillins have a role in NPC1L1-mediated cholesterol uptake and NPC1L1-flotillins-postive cholesterol-enriched membrane microdomains are involved in the mechanism for efficient cholesterol absorption (PMID:21187433)
• dysfunction of the 19 variants on cholesterol absorption is due to the impairment of recycling, subcellular localization, glycosylation, or stability of NPC1L1 (PMID:21189420)
• The structure of NPC1L1(NTD) reveals a degree of flexibility surrounding the entrance to the sterol binding pocket. (PMID:21525977)
• the mechanism of cholesterol sensing by NPC1L1 and proposes a mechanism for selective cholesterol absorption (PMID:21602275)
• These findings demonstrated a direct role of hepatic NPC1L1 in regulating biliary cholesterol excretion and hepatic/blood cholesterol levels, and unequivocally established hepatic NPC1L1 as a target of ezetimibe. (PMID:21683156)
• NPC1L1 down-regulates the expression and secretion of NPC2 by inhibiting its maturation and accelerating its degradation. Hepatic NPC1L1 may control cholesterol homeostasis via the down-regulation of NPC2. (PMID:22095670)
• Lutein absorption is, at least in part, mediated by influx transporters NPC1L1 and SR-B1 rather than mediated by efflux transporters such as ABC (ATP-binding cassette) transporters (PMID:22579005)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	NPC1L1	ENSDARG00000099558
mus_musculus	Npc1l1	ENSMUSG00000020447
rattus_norvegicus	Npc1l1	ENSRNOG00000049955
drosophila_melanogaster	Ptr	FBGN0262867
caenorhabditis_elegans	ptr-17	WBGENE00004231

Paralogs (10): SCAP (ENSG00000114650), PTCH2 (ENSG00000117425), DISP2 (ENSG00000140323), NPC1 (ENSG00000141458), DISP1 (ENSG00000154309), PTCHD1 (ENSG00000165186), PTCHD3 (ENSG00000182077), PTCH1 (ENSG00000185920), DISP3 (ENSG00000204624), PTCHD4 (ENSG00000244694)

Protein

Protein identifiers

NPC1-like intracellular cholesterol transporter 1 — Q9UHC9 (reviewed: Q9UHC9)

Alternative names: Niemann-Pick C1-like protein 1

All UniProt accessions (3): Q9UHC9, A0A0C4DFX6, A0A0C4DGG6

UniProt curated annotations — full annotation on UniProt →

Function. Plays a major role in cholesterol homeostasis. Critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Involved in plant sterol absorption, it transports sitosterol, although at lower rates than cholesterol. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorption and is approved for the treatment of hypercholesterolemia. May have a function in the transport of multiple lipids and their homeostasis, thereby influencing lipid metabolism regulation. May be involved in caveolin trafficking from the plasma membrane. In addition, acts as a negative regulator of NPC2 and down-regulates its expression and secretion by inhibiting its maturation and accelerating its degradation.

Subunit / interactions. Interacts with RAB11A, MYO5B and RAB11FIP2. Interaction with RAB11A, MYO5B and RAB11FIP2 is required for proper transport to the plasma membrane upon cholesterol depletion. Interacts with NPC2. Interacts with LIMA1.

Subcellular location. Apical cell membrane. Cell membrane. Cytoplasmic vesicle membrane.

Tissue specificity. Widely expressed. Expressed in liver. Also expressed in small intestine, pancreas, kidney, lung, pancreas, spleen, heart, gall bladder, brain, testis, stomach and muscle.

Post-translational modifications. Highly glycosylated.

Induction. Expression is decreased in Caco-2 cells upon PPARD activation.

Polymorphism. Genetic variations in NPC1L1 influence low density lipoprotein cholesterol (LDL-C) content defining the low density lipoprotein cholesterol level quantitative trait locus 7 (LDLCQ7) [MIM:617966]. Inactivating variants may confer a lower risk of coronary heart disease. Rare NPC1L1 variants also influence response to ezetimibe, a drug that reduces plasma LDL-C by blocking sterol absorption in enterocytes.

Miscellaneous. Target of cholesterol lowering drugs.

Similarity. Belongs to the patched family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9UHC9-1	1	yes
Q9UHC9-2	2, NPC1L1DELTAE15
Q9UHC9-3	3, NPCL1T
Q9UHC9-4	4

RefSeq proteins (3): NP_001095118, NP_001287896, NP_037521 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000731	SSD	Domain
IPR032190	NPC1_N	Domain
IPR053956	NPC1_MLD	Domain
IPR053958	HMGCR/SNAP/NPC1-like_SSD	Domain

Pfam: PF12349, PF16414, PF22314

Catalyzed reactions (Rhea), 2 shown:

• cholesterol(in) = cholesterol(out) (RHEA:39747)
• sitosterol(out) = sitosterol(in) (RHEA:70723)

UniProt features (185 total): helix 55, strand 41, topological domain 14, disulfide bond 14, sequence variant 14, transmembrane region 13, turn 12, glycosylation site 11, splice variant 4, mutagenesis site 3, signal peptide 1, chain 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
7DFW	ELECTRON MICROSCOPY	2.69
3QNT	X-RAY DIFFRACTION	2.83
7DF8	ELECTRON MICROSCOPY	3.03
7N4X	ELECTRON MICROSCOPY	3.33
7N4U	ELECTRON MICROSCOPY	3.34
7DFZ	ELECTRON MICROSCOPY	3.58
7N4V	ELECTRON MICROSCOPY	3.58

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHC9-F1	84.55	0.49

Functional residue map

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

Disulfide bonds (14): 33–90, 39–57, 78–125, 91–129, 113–254, 116–172, 189–197, 243–259, 256–263, 471–485, 525–542, 920–925, 966–1024, 980–989

Glycosylation sites (11): 54, 132, 138, 244, 416, 431, 464, 479, 497, 506, 626

Mutagenesis-validated functional residues (3):

Position	Phenotype
1300–1303	does not affect interaction with lima1.
1304–1306	abolishes interaction with lima1.
1308–1309	does not affect interaction with lima1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8963678	Intestinal lipid absorption

MSigDB gene sets: 94 (showing top): GOBP_DIGESTION, GOBP_STEROL_HOMEOSTASIS, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOMF_GTPASE_BINDING, GOBP_LIPID_DIGESTION, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_LIPID_HOMEOSTASIS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_STEROID_BIOSYNTHETIC_PROCESS, GOBP_DIGESTIVE_SYSTEM_PROCESS, GOBP_VITAMIN_TRANSPORT, GOBP_LIPID_METABOLIC_PROCESS, GOCC_APICAL_PLASMA_MEMBRANE, GOBP_LIPID_BIOSYNTHETIC_PROCESS, chr7p13

GO Biological Process (15): cholesterol biosynthetic process (GO:0006695), sterol transport (GO:0015918), intestinal cholesterol absorption (GO:0030299), cholesterol transport (GO:0030301), lipoprotein metabolic process (GO:0042157), vitamin E metabolic process (GO:0042360), cholesterol homeostasis (GO:0042632), vitamin transport (GO:0051180), cellular response to sterol depletion (GO:0071501), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202), cholesterol metabolic process (GO:0008203), response to xenobiotic stimulus (GO:0009410), response to muscle activity (GO:0014850), cholesterol import (GO:0070508)

GO Molecular Function (8): vitamin E binding (GO:0008431), cholesterol binding (GO:0015485), small GTPase binding (GO:0031267), myosin V binding (GO:0031489), protein homodimerization activity (GO:0042803), lipid carrier activity (GO:0005319), protein binding (GO:0005515), heterocyclic compound binding (GO:1901363)

GO Cellular Component (7): plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), cytoplasmic vesicle membrane (GO:0030659), endomembrane system (GO:0012505), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), brush border membrane (GO:0031526)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Intestinal absorption	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
lipid transport	1
organic hydroxy compound transport	1
lipid digestion	1
intestinal lipid absorption	1
sterol transport	1
protein metabolic process	1
metabolic process	1
sterol homeostasis	1
transport	1
response to sterol depletion	1
cellular response to stress	1
primary metabolic process	1
lipid metabolic process	1
sterol metabolic process	1
secondary alcohol metabolic process	1
response to chemical	1
response to activity	1
cholesterol transport	1
vitamin binding	1
heterocyclic compound binding	1
sterol binding	1
alcohol binding	1
GTPase binding	1
myosin binding	1
identical protein binding	1
protein dimerization activity	1
molecular carrier activity	1
binding	1
small molecule binding	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
vesicle membrane	1
cytoplasmic vesicle	1
vacuole	1

Protein interactions and networks

STRING

1114 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NPC1L1	CYP7A1	P22680	935
NPC1L1	SCARB1	Q8WTV0	933
NPC1L1	HMGCR	P04035	915
NPC1L1	APOB	P04114	896
NPC1L1	ABCG5	Q9H222	886
NPC1L1	ABCG8	Q9H221	878
NPC1L1	NPC2	P61916	824
NPC1L1	ABCA1	O95477	807
NPC1L1	APOA1	P02647	798
NPC1L1	CETP	P11597	787
NPC1L1	SREBF2	Q12772	723
NPC1L1	PCSK9	Q8NBP7	723
NPC1L1	PLTP	P55058	717
NPC1L1	CD81	P18582	701
NPC1L1	MTTP	P55157	672

IntAct

3 interactions, top by confidence:

A	B	Type	Score
MYC		psi-mi:“MI:0914”(association)	0.350
NPC1L1	MYL12B	psi-mi:“MI:0914”(association)	0.350

BioGRID (47): NPC1L1 (Protein-peptide), NPC1L1 (Affinity Capture-MS), ACTC1 (Affinity Capture-MS), ADAM15 (Affinity Capture-MS), CALM1 (Affinity Capture-MS), CALR (Affinity Capture-MS), CANX (Affinity Capture-MS), CLGN (Affinity Capture-MS), CLPTM1L (Affinity Capture-MS), C3orf58 (Affinity Capture-MS), DNAJB11 (Affinity Capture-MS), DNAJC10 (Affinity Capture-MS), DNAJC16 (Affinity Capture-MS), DNAJC3 (Affinity Capture-MS), ENTPD6 (Affinity Capture-MS)

ESM2 similar proteins: A4IH46, A8I1B9, A8WGF7, B7ZSK1, D4A7H1, F7B113, M0R3Q7, O02721, P02716, P04759, P16235, P16582, P22888, P25110, P26434, P30730, P35436, P40879, Q00959, Q07001, Q0EEE2, Q12879, Q14B62, Q28005, Q28585, Q2M3M2, Q3KNS1, Q3ZC26, Q4KL91, Q4V8B1, Q5IS45, Q5U3U7, Q5XGK0, Q63424, Q6T3U3, Q6T3U4, Q6YBV0, Q811P0, Q8BLV3, Q8BZ00

Diamond homologs: A0A096LPI5, A6NIU2, A6NJG6, P51957, Q5H9K5, Q5T7P6, Q8IV13, Q8N2A0, Q8N9N2, Q96M98, Q96T75, Q9BUA6, Q9UHC9, A0A125YWU9, O15118, O35604, P56941, Q12200, Q6T3U3, Q6T3U4, Q8I266, Q9VRC9, M0R3Q7, Q0EEE2, Q3KNS1

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SREBF2	“up-regulates quantity by expression”	NPC1L1	“transcriptional regulation”
HNF4A	“up-regulates quantity by expression”	NPC1L1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	188
Likely benign	31
Benign	16

Top pathogenic / likely-pathogenic (0)

SpliceAI

3409 predictions. Top by Δscore:

Variant	Effect	Δscore
7:44513645:AGGCC:A	acceptor_gain	1.0000
7:44513646:GGCC:G	acceptor_gain	1.0000
7:44513647:GCC:G	acceptor_gain	1.0000
7:44513648:CC:C	acceptor_gain	1.0000
7:44513648:CCC:C	acceptor_gain	1.0000
7:44513649:CC:C	acceptor_gain	1.0000
7:44513650:C:CC	acceptor_gain	1.0000
7:44513650:CTGCG:C	acceptor_loss	1.0000
7:44513653:C:CT	acceptor_gain	1.0000
7:44515796:CACT:C	donor_loss	1.0000
7:44515797:ACTC:A	donor_loss	1.0000
7:44515798:CTCA:C	donor_loss	1.0000
7:44515800:CA:C	donor_loss	1.0000
7:44515801:A:AC	donor_gain	1.0000
7:44515801:AC:A	donor_gain	1.0000
7:44515801:ACC:A	donor_gain	1.0000
7:44515802:C:CC	donor_gain	1.0000
7:44515802:C:T	donor_loss	1.0000
7:44515802:CC:C	donor_gain	1.0000
7:44515802:CCC:C	donor_gain	1.0000
7:44515802:CCCA:C	donor_gain	1.0000
7:44515806:CGTAG:C	donor_gain	1.0000
7:44515810:G:C	donor_gain	1.0000
7:44515961:AACAC:A	acceptor_gain	1.0000
7:44515962:ACAC:A	acceptor_gain	1.0000
7:44515963:CAC:C	acceptor_gain	1.0000
7:44515963:CACC:C	acceptor_gain	1.0000
7:44516083:CCGCA:C	donor_gain	1.0000
7:44516090:T:TA	donor_gain	1.0000
7:44516091:C:A	donor_gain	1.0000

AlphaMissense

8661 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:44521002:A:G	C1024R	0.999
7:44521785:C:A	W960C	0.999
7:44521785:C:G	W960C	0.999
7:44521001:C:G	C1024S	0.998
7:44521002:A:T	C1024S	0.998
7:44521787:A:G	W960R	0.998
7:44521787:A:T	W960R	0.998
7:44521806:C:A	W953C	0.998
7:44521806:C:G	W953C	0.998
7:44521808:A:G	W953R	0.998
7:44521808:A:T	W953R	0.998
7:44521000:A:C	C1024W	0.997
7:44521027:G:C	F1015L	0.997
7:44521027:G:T	F1015L	0.997
7:44521028:A:C	F1015C	0.997
7:44521029:A:G	F1015L	0.997
7:44521726:C:G	C980S	0.997
7:44521727:A:T	C980S	0.997
7:44539793:A:G	W202R	0.997
7:44539793:A:T	W202R	0.997
7:44539807:C:G	C197S	0.997
7:44539808:A:T	C197S	0.997
7:44540011:C:G	C129S	0.997
7:44540012:A:T	C129S	0.997
7:44540124:G:C	C91W	0.997
7:44540125:C:G	C91S	0.997
7:44540126:A:T	C91S	0.997
7:44540164:C:G	C78S	0.997
7:44540165:A:G	C78R	0.997
7:44540165:A:T	C78S	0.997

dbSNP variants (sampled 300 via entrez): RS1000099419 (7:44529036 A>C), RS1000104535 (7:44513700 T>G), RS1000337435 (7:44516448 A>G,T), RS1000418085 (7:44522272 G>A,C), RS1000496033 (7:44527675 G>T), RS1000553838 (7:44522653 C>A,G,T), RS1000597662 (7:44515343 G>T), RS1000669802 (7:44515039 GTAAAA>G), RS1000823525 (7:44516539 G>A), RS1000905629 (7:44527253 G>A), RS1001045883 (7:44529164 C>T), RS1001139870 (7:44535562 G>A), RS1001182807 (7:44520862 TTC>T), RS1001198186 (7:44525722 A>C), RS1001318566 (7:44535097 G>A,C)

Disease associations

OMIM: gene MIM:608010 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000759_3	LDL cholesterol	4.000000e-11
GCST000760_42	Cholesterol, total	3.000000e-11
GCST002221_1	Cholesterol, total	4.000000e-15
GCST002222_41	LDL cholesterol	7.000000e-16
GCST002896_2	Cholesterol, total	1.000000e-11
GCST002898_25	LDL cholesterol	1.000000e-10
GCST004233_58	LDL cholesterol levels	2.000000e-14
GCST004235_75	Total cholesterol levels	2.000000e-13
GCST007931_21	Medication use (HMG CoA reductase inhibitors)	1.000000e-09
GCST009365_59	LDL cholesterol levels x short total sleep time interaction (2df test)	2.000000e-13
GCST009366_15	LDL cholesterol levels x long total sleep time interaction (2df test)	1.000000e-19
GCST010243_193	Apolipoprotein B levels	1.000000e-31
GCST010245_189	LDL cholesterol levels	2.000000e-40
GCST011346_50	Total cholesterol levels	5.000000e-12
GCST011347_28	Low density lipoprotein cholesterol levels	3.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0004615	apolipoprotein B measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2027 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 29,509 (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
CHEMBL1138	EZETIMIBE	4	29,509

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs17655652	Efficacy	3	pravastatin	Diabetes Mellitus;Hypertension;Vascular Diseases

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17655652	NPC1L1	3	5.50	1	pravastatin
rs2072183	NPC1L1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC65 NPC-type cholesterol transporters

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
ezetimibe	Inhibition	6.66	pKd

ChEMBL bioactivities

106 potent at pChembl≥5 of 136 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.40	IC50	4	nM	CHEMBL578400
8.15	IC50	7	nM	CHEMBL504066
7.70	IC50	20	nM	CHEMBL504066
7.07	EC50	86	nM	CHEMBL3311502
6.82	EC50	150	nM	CHEMBL3311372
6.82	IC50	150	nM	CHEMBL578401
6.70	IC50	200	nM	CHEMBL578401
6.54	EC50	290	nM	CHEMBL3311373
6.52	IC50	300	nM	CHEMBL321017
6.44	EC50	360	nM	CHEMBL3311374
6.44	EC50	360	nM	CHEMBL3311500
6.43	EC50	370	nM	CHEMBL3311498
6.43	IC50	370	nM	EZETIMIBE
6.41	IC50	390	nM	CHEMBL466245
6.25	EC50	560	nM	CHEMBL3311379
6.22	IC50	600	nM	CHEMBL1629905
6.18	IC50	660	nM	CHEMBL466849
6.08	EC50	840	nM	CHEMBL3311378
6.06	EC50	880	nM	CHEMBL3311371
6.05	IC50	900	nM	CHEMBL1632092
6.00	EC50	1000	nM	CHEMBL3311377
6.00	IC50	1000	nM	CHEMBL1629892
6.00	IC50	1000	nM	CHEMBL1631064
5.96	IC50	1100	nM	CHEMBL1632074
5.96	IC50	1100	nM	CHEMBL1632076
5.89	IC50	1300	nM	CHEMBL1629904
5.85	EC50	1400	nM	CHEMBL3311369
5.82	EC50	1500	nM	CHEMBL3311218
5.77	EC50	1700	nM	CHEMBL1277915
5.77	EC50	1700	nM	CHOLESTAN-3beta,5alpha,6beta-TRIOL
5.77	EC50	1700	nM	CHEMBL3311217
5.77	EC50	1700	nM	CHEMBL2418972
5.77	IC50	1700	nM	CHEMBL1631046
5.75	EC50	1800	nM	CHEMBL3311376
5.72	EC50	1900	nM	CHEMBL3311219
5.70	IC50	2000	nM	CHEMBL1631051
5.68	IC50	2100	nM	CHEMBL1631061
5.60	IC50	2500	nM	CHEMBL468523
5.60	IC50	2500	nM	CHEMBL1629902
5.60	IC50	2500	nM	CHEMBL1631042
5.60	IC50	2500	nM	CHEMBL1632088
5.58	IC50	2600	nM	CHEMBL1631072
5.58	IC50	2600	nM	CHEMBL1632077
5.54	EC50	2900	nM	CHEMBL1243244
5.51	EC50	3100	nM	CHEMBL352837
5.51	IC50	3100	nM	CHEMBL1632091
5.51	IC50	3100	nM	CHEMBL1632098
5.51	IC50	3100	nM	CHEMBL1631057
5.50	IC50	3200	nM	CHEMBL1631027
5.48	EC50	3300	nM	CHEMBL169046

PubChem BioAssay actives

106 with measured affinity, of 347 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
(2S,3S,4S,5R,6S)-6-[4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-[3-(methanesulfonamido)prop-1-ynyl]phenyl]-4-oxoazetidin-2-yl]phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid	446838: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human intestinal brush border membrane NPC1L1 by single tube filtration assay	ic50	0.0040	uM
(2S,3S,4S,5R,6S)-6-[4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-[3-(methanesulfonamido)prop-1-ynyl]-4-oxoazetidin-2-yl]phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid	352731: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human recombinant NPC1L1 expressed in HEK293 cells	ic50	0.0070	uM
N-[(2S)-2-[(3S,5R,6R,8S,9S,10R,13S,14S,17R)-5,6-dihydroxy-10,13-dimethyl-3-(2-morpholin-4-yl-2-oxoethoxy)-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]propyl]-3,5-bis(trifluoromethyl)benzamide	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	0.0860	uM
2-[[(3S,5R,6R,8S,9S,10R,13R,14S,17R)-5,6-dihydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]-1-morpholin-4-ylethanone	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	0.1500	uM
(2S,3S,4S,5R,6S)-6-[4-[(2S,3R)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxo-1-(2-tritiophenyl)azetidin-2-yl]-2-tritiophenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid	446838: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human intestinal brush border membrane NPC1L1 by single tube filtration assay	ic50	0.1500	uM
(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-3-(2-morpholin-4-yl-2-oxoethoxy)-1,2,3,4,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-7-one	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	0.2900	uM
(2S,3S,4S,5R,6S)-6-[4-[(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl]phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid	352731: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human recombinant NPC1L1 expressed in HEK293 cells	ic50	0.3000	uM
2-[[(3S,7R,8S,9S,10R,13R,14S,17R)-7-hydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-1-morpholin-4-ylethanone	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	0.3600	uM
2-[[(3S,5R,6R,8S,9S,10R,13R,14S,17R)-17-[(E,2R,5S)-5-ethyl-6-methylhept-3-en-2-yl]-5,6-dihydroxy-10,13-dimethyl-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]-1-morpholin-4-ylethanone	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	0.3600	uM
N-[(2S)-2-[(3S,5R,6R,8S,9S,10R,13S,14S,17R)-5,6-dihydroxy-10,13-dimethyl-3-(2-morpholin-4-yl-2-oxoethoxy)-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]propyl]-2-methylpropanamide	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	0.3700	uM
Ezetimibe	1872307: Inhibition of NPC1L1 (unknown origin) assessed as inhibition of cholesterol cellular uptake by BCA colorimetric assay	ic50	0.3700	uM
[1-(naphthalene-1-carbonyl)-5-phenylpiperidin-3-yl]-spiro[indene-1,4’-piperidine]-1’-ylmethanone	352731: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human recombinant NPC1L1 expressed in HEK293 cells	ic50	0.3900	uM
2-[[(3S,5R,6R,8S,9S,10R,13R,14S,17R)-5,6-dihydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]-N,N-bis(2-hydroxyethyl)acetamide	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	0.5600	uM
(2,2,6,6-tetramethylpiperidin-4-yl) 2-[8-(4-cyclohexylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	0.6000	uM
[(2S,4S)-1-benzoyl-4-phenylpyrrolidin-2-yl]-spiro[indene-1,4’-piperidine]-1’-ylmethanone	352731: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human recombinant NPC1L1 expressed in HEK293 cells	ic50	0.6600	uM
2-[[(3S,5R,6R,8S,9S,10R,13R,14S,17R)-5,6-dihydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]acetamide	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	0.8400	uM
2-[[(3S,8S,9S,10R,13R,14S,17R)-17-[(2R)-6-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-1-morpholin-4-ylethanone	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	0.8800	uM
ethyl 1-[2-[8-(4-cyclohexylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]piperidine-4-carboxylate	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	0.9000	uM
(3S,5R,6R,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-3-(2-morpholin-4-ylethoxy)-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-5,6-diol	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	1.0000	uM
tert-butyl 4-[2-[8-(4-tert-butylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]piperazine-1-carboxylate	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	1.0000	uM
2-[8-(4-tert-butylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2-hydroxyethyl)acetamide	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	1.0000	uM
8-(4-cyclohexylbenzoyl)-3-[2-[4-(hydroxymethyl)piperidin-1-yl]-2-oxoethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	1.1000	uM
8-(4-cyclohexylbenzoyl)-3-(2-oxo-2-piperidin-1-ylethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	1.1000	uM
(2,2,6,6-tetramethylpiperidin-4-yl) 2-[8-(4-tert-butylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetate	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	1.3000	uM
2-[[(3S,8S,9S,10R,13R,14S,17R)-17-[(2R)-6-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl]oxy]-N,N-dimethylacetamide	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	1.4000	uM
(3S,8S,9S,10R,13R,14S,17R)-3-hydroxy-17-[(2R)-6-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-1,2,3,4,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-7-one	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	1.5000	uM
(3S,5R,6R,8S,9S,10R,13R,14S,17R)-17-[(2R)-6-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3,5,6-triol	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	1.7000	uM
(3S,5R,8S,9S,10R,13R,14S,17R)-3,5-dihydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-6-one	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	1.7000	uM
tert-butyl N-[[[2-[8-(4-cyclohexylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]amino]methyl]carbamate	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	1.7000	uM
(4R)-N,N-diethyl-4-[(3S,8S,9S,10R,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanamide	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	1.7000	uM
(3S,5R,6R,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthrene-3,5,6-triol	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	1.7000	uM
2-[[(3S,5R,6R,8S,9S,10R,13R,14S,17R)-5,6-dihydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,3,4,6,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]-1-piperidin-1-ylethanone	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	1.8000	uM
(3S,7R,8S,9S,10R,13R,14S,17R)-17-[(2R)-6-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-3,7-diol	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	1.9000	uM
2-[8-(4-cyclohexylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(2-hydroxyethyl)acetamide	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	2.0000	uM
2-[8-(4-cyclohexylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-N-[2-(methanesulfonamido)ethyl]acetamide	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	2.1000	uM
8-(4-tert-butylbenzoyl)-3-(2-oxo-2-piperidin-1-ylethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	352731: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human recombinant NPC1L1 expressed in HEK293 cells	ic50	2.5000	uM
tert-butyl N-[[1-[2-[8-(4-cyclohexylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]piperidin-4-yl]methyl]carbamate	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	2.5000	uM
8-(4-tert-butylbenzoyl)-3-[2-[4-(2,5-diethyl-4-methylpyrazol-3-yl)piperidin-1-yl]-2-oxoethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	2.5000	uM
methyl 4-[[2-[8-(4-cyclohexylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]amino]butanoate	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	2.5000	uM
8-(4-tert-butylbenzoyl)-3-[2-[4-(2-hydroxyethyl)piperidin-1-yl]-2-oxoethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	2.6000	uM
8-(4-cyclohexylbenzoyl)-3-[2-(3-ethylpiperidin-1-yl)-2-oxoethyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	2.6000	uM
(3S,8S,9S,10R,13S,14S,17R)-17-[(2S,3S)-3-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	2.9000	uM
(4R)-4-[(3S,8S,9S,10R,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]-N,N-dimethylpentanamide	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	3.1000	uM
1-[2-[8-(4-cyclohexylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]piperidine-3-carboxamide	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	3.1000	uM
N-(3-aminopropyl)-2-[8-(4-cyclohexylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetamide	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	3.1000	uM
ethyl 1-[2-[8-(4-tert-butylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]piperidine-4-carboxylate	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	3.1000	uM
2-[8-(4-tert-butylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]-N-(methanesulfonamidomethyl)acetamide	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	3.2000	uM
1-[2-[8-(4-cyclohexylbenzoyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl]acetyl]-N,N-diethylpiperidine-3-carboxamide	548184: Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human NCP1L1 expressed in HEK 293	ic50	3.3000	uM
(3S,8S,9S,10R,13R,14S,17R)-17-[(2R)-6-hydroxy-6-methylheptan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	3.3000	uM
(3S,5S,8S,9S,10R,13R,14S,17R)-3-hydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,3,4,5,7,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-6-one	1179742: Binding affinity to FLAG/tGFP-tagged NPC1 I1061T mutant (unknown origin) expressed in HEK293 cells assessed as localization after 24 hrs by fluorescence microscopy	ec50	3.4000	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Ezetimibe	decreases activity, decreases expression, decreases response to substance	3
Acetaminophen	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cyclosporine	affects expression, decreases expression	2
Aflatoxin B1	increases expression, decreases methylation	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
7-ketocholesterol	decreases expression	1
bisphenol A	increases reaction, increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Zoledronic Acid	increases expression	1
Benzo(a)pyrene	increases mutagenesis	1
Biological Factors	decreases expression	1
Caffeine	decreases phosphorylation	1
Methotrexate	increases expression	1
Rotenone	increases expression, affects cotreatment	1
Stigmasterol	affects cotreatment, increases expression	1
Thiram	increases expression	1
Valproic Acid	decreases expression, increases methylation	1
Cadmium Chloride	increases expression	1
Oleic Acid	decreases expression, affects cotreatment	1
Palmitic Acid	affects cotreatment, decreases expression	1
Okadaic Acid	increases expression	1
Simvastatin	decreases expression	1

ChEMBL screening assays

26 unique, capped per target: 26 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1046285	Binding	Displacement of 35S-6-(4-((2S,3R)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-1-(4-(3-(methylsulfonamido)prop-1-ynyl)phenyl)-4-oxoazetidin-2-yl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid from human intes	Multiple strategies for the preparation of a sulfur-35 labeled NPC1L1 radioligand. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4RK	HuH7-NPC1L1-KO-c6	Cancer cell line	Male

Clinical trials (associated diseases)

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