SMO

Summary

SMO (smoothened, frizzled class receptor, HGNC:11119) is a protein-coding gene on chromosome 7q32.1, encoding Protein smoothened (Q99835). G protein-coupled receptor which associates with the patched protein (PTCH) to transduce hedgehog protein signaling. In precision oncology, SMO Mutation confers sensitivity to Vismodegib in Cancer (CIViC Level B); 7 further curated variant–drug associations are listed below.

The protein encoded by this gene is a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. The encoded protein tranduces signals to other proteins after activation by a hedgehog protein/patched protein complex.

Source: NCBI Gene 6608 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mosaic SMO syndrome (Definitive, ClinGen) — +4 more curated relationships
• Clinical variants (ClinVar): 216 total — 9 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 8 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 7 cancer types
• MANE Select transcript: NM_005631

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11119
Approved symbol	SMO
Name	smoothened, frizzled class receptor
Location	7q32.1
Locus type	gene with protein product
Status	Approved
Aliases	FZD11
Ensembl gene	ENSG00000128602
Ensembl biotype	protein_coding
OMIM	601500
Entrez	6608

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000249373, ENST00000462420, ENST00000475779, ENST00000495998, ENST00000655644, ENST00000925241, ENST00000925242, ENST00000925243, ENST00000925244

RefSeq mRNA: 1 — MANE Select: NM_005631 NM_005631

CCDS: CCDS5811

Canonical transcript exons

ENST00000249373 — 12 exons

Exon	Start	End
ENSE00000882222	129206150	129206369
ENSE00000919470	129205610	129205782
ENSE00000919471	129208759	129208851
ENSE00000919472	129209289	129209397
ENSE00001207377	129188633	129189482
ENSE00001282681	129210965	129211113
ENSE00001282731	129205203	129205412
ENSE00001282739	129203384	129203589
ENSE00001408211	129212024	129213545
ENSE00003511527	129211636	129211770
ENSE00003605879	129210363	129210548
ENSE00003660388	129206464	129206587

Expression profiles

Bgee: expression breadth ubiquitous, 225 present calls, max score 94.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.7912 / max 148.6047, expressed in 1189 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
81007	5.2802	1139
81006	0.5858	365
81009	0.4378	248
81005	0.2386	159
81004	0.1339	61
204694	0.1148	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	94.34	gold quality
left ovary	UBERON:0002119	89.96	gold quality
right ovary	UBERON:0002118	89.74	gold quality
ganglionic eminence	UBERON:0004023	89.36	gold quality
endocervix	UBERON:0000458	89.18	gold quality
pancreatic ductal cell	CL:0002079	88.99	silver quality
ectocervix	UBERON:0012249	87.81	gold quality
body of uterus	UBERON:0009853	87.55	gold quality
adenohypophysis	UBERON:0002196	87.13	gold quality
right lobe of liver	UBERON:0001114	87.07	gold quality
metanephros cortex	UBERON:0010533	86.45	gold quality
pituitary gland	UBERON:0000007	85.69	gold quality
apex of heart	UBERON:0002098	85.61	gold quality
sural nerve	UBERON:0015488	85.19	gold quality
ovary	UBERON:0000992	85.03	gold quality
tibial nerve	UBERON:0001323	84.73	gold quality
lower esophagus mucosa	UBERON:0035834	84.47	gold quality
embryo	UBERON:0000922	84.28	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.26	gold quality
skin of abdomen	UBERON:0001416	84.13	gold quality
left uterine tube	UBERON:0001303	83.67	gold quality
vagina	UBERON:0000996	83.10	gold quality
right uterine tube	UBERON:0001302	82.88	gold quality
skin of leg	UBERON:0001511	82.70	gold quality
minor salivary gland	UBERON:0001830	81.93	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	81.76	gold quality
lower esophagus	UBERON:0013473	81.53	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.51	gold quality
ascending aorta	UBERON:0001496	81.41	gold quality
thoracic aorta	UBERON:0001515	81.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	180.95
E-ANND-3	yes	3.44

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
GLI1	Activation
MAG	Activation
MAL	Activation
MBP	Activation
MMP9	Activation
OPALIN	Activation
TIMP3	Activation

Upstream regulators (CollecTRI, top): GLI3, MBD2, NME1

miRNA regulators (miRDB)

41 targeting SMO, 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-4455	100.00	65.48	1587
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-657	99.48	66.02	848
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-5008-5P	98.42	65.87	1019
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-6072	98.00	66.47	804

Literature-anchored findings (GeneRIF, showing 40)

• results suggest that the Ptc tumour suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity (PMID:12192414)
• smoothened expression in human astrocytic tumors inversely correlates with histological malignancy (PMID:12241103)
• Significantly high levels of ultraviolet-specific mutations in the smoothened gene are found in basal cell carcinomas from DNA repair-deficient xeroderma pigmentosum patients. (PMID:12499255)
• role of the human M2SMO mutant in BCC development in adult transgenic mice (PMID:12773389)
• beta-Arrestin 2 and GRK2 are potential mediators of signaling by activated Smoothened (PMID:15618519)
• overexpression and/or tumorigenic activation of the Smo proto-oncogene mediates c-myc overexpression which plays a critical role in hepatocarcinogenesis; study suggests that Smo is a prognostic factor in HCC tumorigenesis (PMID:16339184)
• aberrant expressions of PTCH and Smo were common in pancreatic carcinoma tissues & were associated with low-level differentiation of tumor tissue & hyperglycemia; this indicated that these molecules played a fundamental role in pancreas tumorigenesis (PMID:16804411)
• the upstream part of the Hedgehog pathway involving Hedgehog interaction with Patched, regulation of Smoothened by Patched, and Smoothened enrichment at the plasma membrane is highly conserved between Drosophila and humans (PMID:16867986)
• analysis of Hedgehog modulator properties after functional coupling of Smoothened to G15 (PMID:16945339)
• Specific siRNA can significantly decrease Smo mRNA expression and inhibit the proliferation while inducing apoptosis of LoVo cells. (PMID:17884791)
• Smo mutants augment p53 binding to the E3 ubiquitin-protein ligase Mdm2 and promote p53 ubiquitination. (PMID:18359851)
• mutations are rare in SMO in sporadic and nevoid basal cell carcinoma syndrome-associated keratocystic odontogenic tumors (PMID:18502968)
• Constitutive activation of the hedgehog signaling pathway in chondrosarcoma is rarely caused by SMO protein mutation. (PMID:18543049)
• The interactions of small molecule agonists and antagonists with SMO were characterized. (PMID:19304771)
• the expression of Smoothened was very low or almost absent In the normal endometrium and significantly highly expressed in complex and atypical hyperplasia (PMID:19432668)
• investigated immunohistochemical expression of sonic hedgehog signaling pathway-related proteins, PTCH, smoothened (SMO) and GLI-1 in a series of primary OKC, recurrent OKC (rOKC) and nevoid basal cell carcinoma syndrome-associated OKCs (PMID:19473442)
• Studies suggest that Hh binding to Ptc leads to the de-repression of the GPCR-related protein Smo. (PMID:19564910)
• study identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway (PMID:19726788)
• SMO is preferentially expressed by human bulge cells, compared to differentiated hair follicle keratinocytes (PMID:20050020)
• Knockdown of SMO by SMO shRNA prevents osteosarcoma growth in vitro and in vivo. (PMID:20067614)
• Overexpression of SMO activates the sonic hedgehog signaling pathway and is associated with pancreatic cancer. (PMID:20215540)
• proteins of the SHH signaling pathway are predominantly located within the epithelial components of GOCs and DCs. SHH signaling pathway may play a role in epithelial lining formation. (PMID:20561215)
• functional role of SMOH and GLI in cell survival (PMID:20603613)
• The expression level of SMO in NPC is generally high, but the expression level of PTCH-1 was relatively low. (PMID:20937227)
• We found that hedgehog-interacting protein, PDGFRalpha, SMO and Su(Fu) gene highly expressed in the primary esophageal squamous cell carcinomas (PMID:21210262)
• hypoxia induces upregulation of Smo transcription, consequently increasing Hh pathway activation in a ligand-independent manner and enhancing the invasiveness of pancreatic cancer. (PMID:21338440)
• alpha subunit of the G protein G13 regulates activity of one or more Gli transcription factors independently of smoothened (PMID:21757753)
• Sonic Hedgehog activates the GTPases Rac1 and RhoA in a Gli-independent manner through coupling of smoothened to Gi proteins. (PMID:22114142)
• the effects of oxysterols on Hedgehog signaling are exquisitely stereoselective, consistent with the hypothesis that they function through a specific protein target. (PMID:22231273)
• USP8 is a positive regulator in Hh signaling by down-regulating Smo ubiquitination and thereby mediating Smo intracellular trafficking. (PMID:22253573)
• Results suggest that hypoxia-induced increase of Smo directly contributes to the proliferation of pancreatic ductal adenocarcinoma (PDAC) cells through a hedgehog/Gli1-independent pathway. (PMID:22486854)
• The immunoexpression of Shh, Smo and Gli2 proteins was lower in Helicobacter pylori-positive group compared to Helicobacter pylori-negative group (PMID:22535603)
• different pools of Smo move into cilia through distinct mechanisms (PMID:22864913)
• High SMO expression is associated with colorectal cancer. (PMID:22901214)
• Study shows that hedgehog signaling rewires cellular metabolism; Smo-dependent noncanonical signal rewires metabolism in vitro and in vivo. (PMID:23063129)
• High SMO expression is asociated with postoperative liver metastasis in colon cancer. (PMID:23098507)
• A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. (PMID:23334667)
• downregulation of miR-326 may be a possible mechanism for unrestricted activation of Smo signal transducer of the oncogenic Hedgehog pathway in chronic myeloid leukemia (PMID:23341351)
• SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas (PMID:23348505)
• SMO and/or PTCH1 mutations are present at low frequency in different histologic subtypes of gastric tumors and these do not appear to be driver mutations. (PMID:23349881)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	smo	ENSDARG00000002952
mus_musculus	Smo	ENSMUSG00000001761
rattus_norvegicus	Smo	ENSRNOG00000008332
drosophila_melanogaster	smo	FBGN0003444

Paralogs (15): FZD3 (ENSG00000104290), SFRP1 (ENSG00000104332), SFRP4 (ENSG00000106483), FZD10 (ENSG00000111432), SFRP5 (ENSG00000120057), SFRP2 (ENSG00000145423), FZD7 (ENSG00000155760), FZD1 (ENSG00000157240), FRZB (ENSG00000162998), FZD5 (ENSG00000163251), FZD6 (ENSG00000164930), FZD4 (ENSG00000174804), FZD8 (ENSG00000177283), FZD2 (ENSG00000180340), FZD9 (ENSG00000188763)

Protein

Protein identifiers

Protein smoothened — Q99835 (reviewed: Q99835)

Alternative names: Protein Gx

All UniProt accessions (4): Q99835, A0A590UJE7, H7C509, H7C5S9

UniProt curated annotations — full annotation on UniProt →

Function. G protein-coupled receptor which associates with the patched protein (PTCH) to transduce hedgehog protein signaling. Binding of sonic hedgehog (SHH) to its receptor patched prevents inhibition of smoothened (SMO) by patched. When active, SMO binds to and sequesters protein kinase A catalytic subunit PRKACA at the cell membrane, preventing PRKACA-mediated phosphorylation of GLI transcription factors which releases the GLI proteins from PRKACA-mediated inhibition and allows for transcriptional activation of hedgehog pathway target genes. Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia. Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation.

Subunit / interactions. Homodimer. Interacts (via C-terminus) with protein kinase A catalytic subunit PRKACA; interacts with free PRKACA subunits and the interaction leads to sequestration of PRKACA at the membrane, preventing PRKACA-mediated phosphorylation of GLI transcription factors. Interacts with ARRB2. Interacts with KIF7. Interacts with BBS5 and BBS7; the interactions are indicative for the association of SMO with the BBsome complex to facilitate ciliary localization of SMO. Interacts with DLG5 and SDCBP. Interacts with DRC4.

Subcellular location. Cell membrane. Cell projection. Cilium.

Post-translational modifications. Phosphorylation by GRK kinases is required for interaction with protein kinase A catalytic subunit PRKACA.

Disease relevance. Curry-Jones syndrome (CRJS) [MIM:601707] A multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. The disease is caused by variants affecting the gene represented in this entry. 8 individuals have been identified with the disease-causing mutation Phe-412 and all were mosaic. The mutation could not be reliably detected in blood, greatest success rates were obtained with affected tissues obtained by invasive procedures. It is thought that the mutation has arisen postzygotically early during embryonic development. This mutation has also been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and has been reported as the oncogenic driver in some of these tumors.

Domain organisation. The N-terminal extracellular domain mediates sterol-binding which is required for maximal activation of signaling. Contains a second sterol-binding site within the seven-transmembrane pocket which is also required for activation. The activating sterol is likely to be cholesterol. The extracellular site is required for SHH-induced activity while the site within the transmembrane pocket regulates basal signaling in the absence of SHH.

Similarity. Belongs to the G-protein coupled receptor Fz/Smo family.

RefSeq proteins (1): NP_005622* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000539	Frizzled/Smoothened_7TM	Domain
IPR015526	Frizzled/SFRP	Family
IPR017981	GPCR_2-like_7TM	Domain
IPR020067	Frizzled_dom	Domain
IPR035683	SMO_7TM	Domain
IPR036790	Frizzled_dom_sf	Homologous_superfamily
IPR041771	SMO_CRD	Domain

Pfam: PF01392, PF01534

UniProt features (98 total): helix 20, strand 18, modified residue 9, disulfide bond 9, topological domain 8, transmembrane region 7, turn 7, region of interest 5, sequence variant 4, compositionally biased region 3, glycosylation site 3, binding site 2, signal peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
4JKV	X-RAY DIFFRACTION	2.45
4QIN	X-RAY DIFFRACTION	2.6
4QIM	X-RAY DIFFRACTION	2.61
4N4W	X-RAY DIFFRACTION	2.8
5V56	X-RAY DIFFRACTION	2.9
5V57	X-RAY DIFFRACTION	3
7ZI0	X-RAY DIFFRACTION	3
6XBM	ELECTRON MICROSCOPY	3.14
5L7D	X-RAY DIFFRACTION	3.2
4O9R	X-RAY DIFFRACTION	3.2
6XBK	ELECTRON MICROSCOPY	3.24
5L7I	X-RAY DIFFRACTION	3.3
6OT0	ELECTRON MICROSCOPY	3.84
6XBJ	ELECTRON MICROSCOPY	3.88
6XBL	ELECTRON MICROSCOPY	3.96

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99835-F1	73.55	0.43

Antibody-complex structures (SAbDab): 5 — 6OT0, 6XBJ, 6XBK, 6XBL, 6XBM

Functional residue map

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

Ligand- & substrate-binding residues (2): 95; 394

Post-translational modifications (9): 556, 574, 590, 593, 595, 638, 640, 644, 662

Disulfide bonds (9): 64–178, 70–134, 78–127, 118–154, 147–169, 193–213, 217–295, 314–390, 490–507

Glycosylation sites (3): 35, 188, 309

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-5620922	BBSome-mediated cargo-targeting to cilium
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-5635838	Activation of SMO
R-HSA-162582	Signal Transduction
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-372790	Signaling by GPCR
R-HSA-500792	GPCR ligand binding
R-HSA-5358351	Signaling by Hedgehog
R-HSA-5617833	Cilium Assembly
R-HSA-5620920	Cargo trafficking to the periciliary membrane

MSigDB gene sets: 833 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_METANEPHRIC_NEPHRON_MORPHOGENESIS, GOBP_DENTATE_GYRUS_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_AXIS_SPECIFICATION, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, GOBP_METANEPHROS_DEVELOPMENT

GO Biological Process (89): negative regulation of transcription by RNA polymerase II (GO:0000122), vasculogenesis (GO:0001570), osteoblast differentiation (GO:0001649), in utero embryonic development (GO:0001701), cell fate specification (GO:0001708), neural crest cell migration (GO:0001755), negative regulation of protein phosphorylation (GO:0001933), heart looping (GO:0001947), positive regulation of neuroblast proliferation (GO:0002052), positive regulation of mesenchymal cell proliferation (GO:0002053), determination of left/right asymmetry in lateral mesoderm (GO:0003140), type B pancreatic cell development (GO:0003323), protein import into nucleus (GO:0006606), apoptotic process (GO:0006915), smoothened signaling pathway (GO:0007224), ventral midline determination (GO:0007371), pattern specification process (GO:0007389), neuroblast proliferation (GO:0007405), central nervous system development (GO:0007417), midgut development (GO:0007494), anterior/posterior pattern specification (GO:0009952), gene expression (GO:0010467), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), spinal cord dorsal/ventral patterning (GO:0021513), dentate gyrus development (GO:0021542), cerebellar cortex morphogenesis (GO:0021696), thalamus development (GO:0021794), dorsal/ventral neural tube patterning (GO:0021904), regulation of cerebellar granule cell precursor proliferation (GO:0021936), central nervous system neuron differentiation (GO:0021953), cerebral cortex development (GO:0021987), positive regulation of cell migration (GO:0030335), negative regulation of epithelial cell differentiation (GO:0030857), hair follicle morphogenesis (GO:0031069), multicellular organism growth (GO:0035264), positive regulation of multicellular organism growth (GO:0040018), positive regulation of protein import into nucleus (GO:0042307), odontogenesis of dentin-containing tooth (GO:0042475), negative regulation of apoptotic process (GO:0043066)

GO Molecular Function (8): cAMP-dependent protein kinase inhibitor activity (GO:0004862), G protein-coupled receptor activity (GO:0004930), patched binding (GO:0005113), oxysterol binding (GO:0008142), protein kinase A catalytic subunit binding (GO:0034236), protein sequestering activity (GO:0140311), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (18): late endosome (GO:0005770), endoplasmic reticulum (GO:0005783), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), Golgi apparatus (GO:0005794), centriole (GO:0005814), plasma membrane (GO:0005886), cilium (GO:0005929), dendrite (GO:0030425), endocytic vesicle membrane (GO:0030666), ciliary membrane (GO:0060170), extracellular exosome (GO:0070062), ciliary tip (GO:0097542), 9+0 non-motile cilium (GO:0097731), cytoplasm (GO:0005737), caveola (GO:0005901), membrane (GO:0016020), cell projection (GO:0042995), plasma membrane bounded cell projection (GO:0120025)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Signaling by Hedgehog	2
Signal Transduction	2
GPCR ligand binding	1
Cargo trafficking to the periciliary membrane	1
Hedgehog ‘on’ state	1
Signaling by GPCR	1
Organelle biogenesis and maintenance	1
Assembly of the 9+0 primary cilium	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
intracellular membrane-bounded organelle	3
cell differentiation	2
endomembrane system	2
bounding membrane of organelle	2
cilium	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
ossification	1
chordate embryonic development	1
cell fate commitment	1
cellular developmental process	1
neural crest cell development	1
mesenchymal cell migration	1
regulation of protein phosphorylation	1
protein phosphorylation	1
negative regulation of protein modification process	1
negative regulation of phosphorylation	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
determination of left/right symmetry	1
lateral mesoderm development	1
epithelial cell development	1
type B pancreatic cell differentiation	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
programmed cell death	1
apoptotic signaling pathway	1

Protein interactions and networks

STRING

2758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMO	PTCH1	Q13635	999
SMO	SHH	Q15465	999
SMO	IHH	Q14623	996
SMO	SUFU	Q9UMX1	984
SMO	KIF3A	Q9Y496	983
SMO	GLI1	P08151	975
SMO	ARRB2	P32121	959
SMO	GLI2	P10070	954
SMO	GLI3	P10071	945
SMO	DHH	O43323	924
SMO	ARRB1	P49407	917
SMO	RAB23	Q9ULC3	871
SMO	KIF7	Q2M1P5	869
SMO	IFT88	Q13099	864
SMO	PTCH2	Q9Y6C5	846

IntAct

64 interactions, top by confidence:

A	B	Type	Score
GNG2	GNB1	psi-mi:“MI:0915”(physical association)	0.910
KCNJ2	KCNJ18	psi-mi:“MI:2364”(proximity)	0.660
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
PTCH1	SMO	psi-mi:“MI:0914”(association)	0.430
SMO	Rps27a	psi-mi:“MI:0915”(physical association)	0.400
SMO	RpL40	psi-mi:“MI:0915”(physical association)	0.400
ARV1	SMO	psi-mi:“MI:0915”(physical association)	0.370
C18orf32	SMO	psi-mi:“MI:0915”(physical association)	0.370
EMC10	SMO	psi-mi:“MI:0915”(physical association)	0.370
TIMMDC1	SMO	psi-mi:“MI:0915”(physical association)	0.370
S1PR5	SMO	psi-mi:“MI:0915”(physical association)	0.370
FKBP8	SMO	psi-mi:“MI:0915”(physical association)	0.370
WLS	SMO	psi-mi:“MI:0915”(physical association)	0.370
GABARAPL2	SMO	psi-mi:“MI:0915”(physical association)	0.370
GABBR1	SMO	psi-mi:“MI:0915”(physical association)	0.370
ARLN	SMO	psi-mi:“MI:0915”(physical association)	0.370
HMOX1	SMO	psi-mi:“MI:0915”(physical association)	0.370
HMOX2	SMO	psi-mi:“MI:0915”(physical association)	0.370
HMGN4	SMO	psi-mi:“MI:0915”(physical association)	0.370
ITGB1BP1	SMO	psi-mi:“MI:0915”(physical association)	0.370
JPH3	SMO	psi-mi:“MI:0915”(physical association)	0.370
LEPROT	SMO	psi-mi:“MI:0915”(physical association)	0.370
NDFIP1	SMO	psi-mi:“MI:0915”(physical association)	0.370
NGEF	SMO	psi-mi:“MI:0915”(physical association)	0.370
NIPA1	SMO	psi-mi:“MI:0915”(physical association)	0.370
PLPP7	SMO	psi-mi:“MI:0915”(physical association)	0.370
RPN2	SMO	psi-mi:“MI:0915”(physical association)	0.370
SSPN	SMO	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (60): SMO (Negative Genetic), SMO (Negative Genetic), SMO (Positive Genetic), SMO (Affinity Capture-MS), GNAI1 (Co-crystal Structure), GNB1 (Co-crystal Structure), GNGT1 (Co-crystal Structure), SMO (Affinity Capture-Western), HERC4 (Affinity Capture-Western), ADRBK1 (Affinity Capture-Western), SMO (Affinity Capture-Western), SMO (Affinity Capture-Western), SMO (Proximity Label-MS), SMO (Proximity Label-MS), SMO (Proximity Label-MS)

ESM2 similar proteins: A0JPH4, A2AWP8, A2RRU4, A2SXS5, A4D2P6, A6QM06, D4A6L0, E1BBQ2, E9Q6C8, F1LQY6, O00255, O88559, O94827, P29590, P56726, P97260, P97698, Q0GA42, Q0P5I0, Q0VF94, Q12770, Q17RQ9, Q29RM4, Q49LS8, Q5GH57, Q5GH73, Q5MNU5, Q5SNT2, Q5T848, Q69Z89, Q6DVA0, Q6GQT6, Q6IEE7, Q70EL4, Q8BUM9, Q8C190, Q8C419, Q8NC56, Q8TCT7, Q91ZP9

Diamond homologs: O42224, P56726, P91682, P97698, Q5RH73, Q99835, Q9IA03, Q9VVX3, Q5T4F7, Q9WU66, Q9XSC1, Q66K79, A0A0K3AWM6, B3DIG4, G5ECQ2, O00144, O42579, O57328, O57329, O60353, O70421, O75084, O93274, P18537, P58421, Q08463, Q08464, Q13467, Q14332, Q24760, Q498S8, Q5BL72, Q5RCN4, Q61086, Q61088, Q61089, Q61090, Q61091, Q8AVJ9, Q8BKG4

SIGNOR signaling

77 interactions.

A	Effect	B	Mechanism
PTCH1	“down-regulates activity”	SMO	binding
GRK2	up-regulates	SMO	phosphorylation
SMO	up-regulates	ARRB1	binding
SMO	up-regulates	ARRB2	binding
Jervine	down-regulates	SMO	“chemical inhibition”
CP	down-regulates	SMO	binding
SMO	up-regulates	CXCL1	binding
SMO	up-regulates	GNAI3	binding
SMO	up-regulates	GNAT1	binding
SMO	up-regulates	GNAT2	binding
SMO	up-regulates	GNB1	binding
SMO	up-regulates	GNB2	binding
SMO	up-regulates	GNB3	binding
SMO	up-regulates	GNG2	binding
SMO	up-regulates	GNG3	binding
SMO	up-regulates	GNGT1	binding
SMO	up-regulates	STK36	binding
SMO	up-regulates	GNG12	binding
purmorphamine	up-regulates	SMO	“chemical activation”
SMO	up-regulates	TIAM1	binding
vismodegib	down-regulates	SMO	“chemical inhibition”
sonidegib	down-regulates	SMO	“chemical inhibition”
Cyclopamine	down-regulates	SMO	“chemical inhibition”
CSNK1A1	up-regulates	SMO	phosphorylation
SMO	“down-regulates activity”	SUFU	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Hedgehog ‘on’ state	5	18.9×	8e-04
Ub-specific processing proteases	7	8.8×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of ERK1 and ERK2 cascade	6	9.5×	5e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	7	6.8×	6e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 7 cancer types — BCC, GB, HCC, MBL, PAST, PLMESO, SKIN.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	2
Uncertain significance	116
Likely benign	40
Benign	23

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
245609	NM_005631.5(SMO):c.1234C>T (p.Leu412Phe)	Pathogenic
8117	NM_005631.5(SMO):c.1604G>T (p.Trp535Leu)	Pathogenic
8118	NM_005631.5(SMO):c.1685G>A (p.Arg562Gln)	Pathogenic
975032	NM_005631.5(SMO):c.2291_2292del (p.Gln764fs)	Pathogenic
975033	NM_005631.5(SMO):c.781C>T (p.Arg261Cys)	Pathogenic
975034	NM_005631.5(SMO):c.1339G>T (p.Glu447Ter)	Pathogenic
975035	NM_005631.5(SMO):c.1727G>A (p.Arg576Gln)	Pathogenic
975036	NM_005631.5(SMO):c.1726C>T (p.Arg576Trp)	Pathogenic
975037	NM_005631.5(SMO):c.1285A>T (p.Ile429Phe)	Pathogenic
982409	NM_005631.5(SMO):c.754T>C (p.Phe252Leu)	Likely pathogenic
982410	NM_005631.5(SMO):c.1198C>T (p.Arg400Cys)	Likely pathogenic

SpliceAI

1833 predictions. Top by Δscore:

Variant	Effect	Δscore
7:129189478:GTCGG:G	donor_gain	1.0000
7:129189480:CGGG:C	donor_loss	1.0000
7:129189481:GG:G	donor_gain	1.0000
7:129189482:GG:G	donor_gain	1.0000
7:129189483:G:A	donor_loss	1.0000
7:129189483:G:GG	donor_gain	1.0000
7:129189484:T:TC	donor_loss	1.0000
7:129202614:ACT:A	acceptor_gain	1.0000
7:129203590:G:GA	donor_loss	1.0000
7:129203592:GAGT:G	donor_loss	1.0000
7:129205194:T:A	acceptor_gain	1.0000
7:129205195:G:A	acceptor_gain	1.0000
7:129205338:GC:G	donor_gain	1.0000
7:129205350:G:GT	donor_gain	1.0000
7:129205361:C:G	donor_gain	1.0000
7:129205461:G:GT	donor_gain	1.0000
7:129205461:G:T	donor_gain	1.0000
7:129205606:CTAG:C	acceptor_loss	1.0000
7:129205607:TAG:T	acceptor_loss	1.0000
7:129205608:A:AG	acceptor_gain	1.0000
7:129205608:A:AT	acceptor_loss	1.0000
7:129205608:AG:A	acceptor_gain	1.0000
7:129205609:G:GA	acceptor_gain	1.0000
7:129205609:GG:G	acceptor_gain	1.0000
7:129205609:GGC:G	acceptor_gain	1.0000
7:129205609:GGCC:G	acceptor_gain	1.0000
7:129205609:GGCCA:G	acceptor_gain	1.0000
7:129205780:CACG:C	donor_loss	1.0000
7:129205783:G:GG	donor_gain	1.0000
7:129205783:GTA:G	donor_loss	1.0000

AlphaMissense

5096 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:129203405:G:A	C118Y	1.000
7:129203409:G:C	W119C	1.000
7:129203409:G:T	W119C	1.000
7:129203491:T:A	C147S	1.000
7:129203492:G:C	C147S	1.000
7:129203513:G:A	C154Y	1.000
7:129203539:T:A	W163R	1.000
7:129203539:T:C	W163R	1.000
7:129203541:G:C	W163C	1.000
7:129203541:G:T	W163C	1.000
7:129203549:T:G	F166C	1.000
7:129205242:T:A	C193S	1.000
7:129205242:T:C	C193R	1.000
7:129205243:G:C	C193S	1.000
7:129205302:T:A	C213S	1.000
7:129205302:T:C	C213R	1.000
7:129205303:G:A	C213Y	1.000
7:129205303:G:C	C213S	1.000
7:129205314:T:A	C217S	1.000
7:129205315:G:C	C217S	1.000
7:129205616:T:C	F252L	1.000
7:129205618:C:A	F252L	1.000
7:129205618:C:G	F252L	1.000
7:129205675:T:A	N271K	1.000
7:129205675:T:G	N271K	1.000
7:129205745:T:A	C295S	1.000
7:129205746:G:C	C295S	1.000
7:129206170:G:A	C314Y	1.000
7:129206181:T:C	F318L	1.000
7:129206183:T:A	F318L	1.000

dbSNP variants (sampled 300 via entrez): RS1000193026 (7:129193245 C>T), RS1000395646 (7:129208630 G>A), RS1000430358 (7:129205498 G>A), RS1000533713 (7:129194869 C>T), RS1000724557 (7:129200550 G>A), RS1000760243 (7:129206807 C>T), RS1000789130 (7:129199280 A>G), RS1000918443 (7:129190035 A>G), RS1001059830 (7:129189754 G>C), RS1001131402 (7:129188521 A>T), RS1001147794 (7:129196799 C>T), RS1001479504 (7:129188741 T>C), RS1001515531 (7:129196679 A>C,G), RS1001663534 (7:129212613 T>G), RS1001730443 (7:129193188 G>T)

Disease associations

OMIM: gene MIM:601500 | disease phenotypes: MIM:241800, MIM:601707, MIM:605462

GenCC curated gene-disease

Disease	Classification	Inheritance
Curry-Jones syndrome	Definitive	Autosomal dominant
congenital hypothalamic hamartoma syndrome	Strong	Autosomal recessive
Hirschsprung disease	Supportive	Autosomal dominant
medulloblastoma	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
congenital hypothalamic hamartoma syndrome	Moderate	AR
mosaic SMO syndrome	Definitive	AD

Mondo (7): congenital hypothalamic hamartoma syndrome (MONDO:0009436), Curry-Jones syndrome (MONDO:0011134), basal cell carcinoma, susceptibility to, 1 (MONDO:0011556), coloboma (MONDO:0001476), microcephaly (MONDO:0001149), medulloblastoma (MONDO:0007959), Hirschsprung disease (MONDO:0018309)

Orphanet (3): Curry-Jones syndrome (Orphanet:1553), OBSOLETE: Ocular coloboma (Orphanet:194), Congenital hypothalamic hamartoma syndrome (Orphanet:2113)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D003103	Coloboma	C11.250.110; C11.270.147; C16.131.384.282
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D008527	Medulloblastoma	C04.557.465.625.600.380.515; C04.557.465.625.600.590.500; C04.557.470.670.380.515; C04.557.470.670.590.500; C04.557.580.625.600.380.515; C04.557.580.625.600.590.500
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C537158	Hypothalamic hamartomas (supp.)
C536735	Winter Shortland Temple syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5971 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 25,380 (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
CHEMBL1852688	INFIGRATINIB	4	2,209
CHEMBL2105737	SONIDEGIB	4	3,859
CHEMBL3137317	SONIDEGIB PHOSPHATE	4	1,623
CHEMBL473417	VISMODEGIB	4	6,714
CHEMBL223360	LINIFANIB	3	3,925
CHEMBL538867	PATIDEGIB	3	1,695
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL2029988	CEP-32496	2	1,136
CHEMBL2142592	TALADEGIB	2	529
CHEMBL2205230	TAK-441	1	120
CHEMBL3133037	LEQ506	1	474

Clinical evidence (CIViC)

Drug × variant × indication: 8 predictive associations from 11 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
SMO Mutation	Vismodegib	Cancer	Sensitivity/Response	CIViC B	EID5979
SMO Mutation	Vismodegib + Sonidegib	Basal Cell Carcinoma	Resistance	CIViC B	EID1477
SMO Mutation	Vismodegib	Basal Cell Carcinoma	Resistance	CIViC B	EID746
SMO L412F	Vismodegib	Basal Cell Carcinoma	Resistance	CIViC C	EID4654 +2
SMO D473H	Vismodegib	Medulloblastoma	Resistance	CIViC C	EID745 +1
SMO D473H	Patidegib	Medulloblastoma	Sensitivity/Response	CIViC D	EID1099
SMO Mutation	Arsenic Trioxide + PSI	Basal Cell Carcinoma	Sensitivity/Response	CIViC D	EID747
SMO D473H	Vismodegib	Basal Cell Carcinoma	Resistance	CIViC D	EID755

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Class Frizzled GPCRs

Most potent curated ligand interactions (16 total), top 16:

Ligand	Action	Affinity	Parameter
MRT-92	Antagonist	9.52	pKd
saridegib	Antagonist	8.85	pIC50
SAG1.3	Agonist	8.52	pEC50
AZD8542	Antagonist	8.52	pIC50
TAK-441	Antagonist	8.36	pIC50
glasdegib	Antagonist	8.3	pIC50
sonidegib	Antagonist	8.22	pKi
taladegib	Antagonist	8.2	pIC50
ANTA XV	Antagonist	8.15	pIC50
vismodegib	Antagonist	7.79	pKi
cyclopamine-KAAD	Antagonist	7.7	pIC50
SANT-1	Antagonist	7.7	pKi
SANT-2	Antagonist	7.52	pIC50
cyclopamine	Antagonist	7.0	pIC50
purmorphamine	Agonist	6.0	pEC50
GSA-10	Positive	5.92	pEC50

Binding affinities (BindingDB)

149 measured of 149 human assays (149 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[1-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	6.4 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]-3-methylsulfonylpropan-1-one	IC50	6.8 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[5-chloro-4-(5-fluoro-3-methyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]-3-methylsulfonylpropan-1-one	IC50	7.11 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[5-chloro-4-(3-methyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]-3-methylsulfonylpropan-1-one	IC50	9.84 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(5-fluoro-3-methyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]-2-hydroxy-2-methylpropane-1-sulfonamide	IC50	10.6 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
[1-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	11.1 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[5-chloro-4-(5-fluoro-3-methyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]sulfonyl-2-methylpropan-2-ol	IC50	11.4 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]cyclopropanesulfonamide	IC50	11.5 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]ethanesulfonamide	IC50	11.6 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]-3-methylsulfonylpropan-1-one	IC50	11.6 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-[4-[4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]ethanone	IC50	12.1 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	12.2 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
2-[5-chloro-2-[4-(methylsulfonylmethyl)piperidin-1-yl]-4-pyridinyl]-3,5-dimethylpyridine	IC50	12.4 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]-3-methylsulfonylpropanamide	IC50	14.7 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]-2-morpholin-4-ylethanone	IC50	14.8 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-(5-chloro-6-pyridin-2-yl-2-pyridinyl)piperidin-4-yl]-2-hydroxyethanesulfonamide	IC50	15.2 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-(5-chloro-6-pyridin-2-yl-2-pyridinyl)piperidin-4-yl]cyclopropanesulfonamide	IC50	16.5 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-6-(5-methyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	17 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[4-(3-methyl-2-pyridinyl)pyrimidin-2-yl]piperidin-4-yl]methanesulfonamide	IC50	17.7 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-3-fluoro-2-pyridinyl]piperidin-4-yl]-3-methylsulfonylpropanamide	IC50	17.8 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(3-methyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	18.7 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(3,5-dichloro-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	18.8 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]-2-(dimethylamino)acetamide	IC50	19.2 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]-3-hydroxy-3-methylbutan-1-one	IC50	19.4 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[4-(3,5-dimethyl-2-pyridinyl)-5-fluoro-2-pyridinyl]piperazin-1-yl]-3-methylsulfonylpropan-1-one	IC50	20.4 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(5-chloro-3-methyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	20.5 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-6-(3-methyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	20.6 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(5-fluoro-3-methyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]-2-hydroxyethanesulfonamide	IC50	20.7 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(5-fluoro-3-methyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	20.8 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[5-chloro-4-(3-methyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]-3-hydroxy-3-methylbutan-1-one	IC50	21.7 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[6-(5-methyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	22 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[5-chloro-6-(5-methyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]-3-methylsulfonylpropan-1-one	IC50	22.5 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
2-[4-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]sulfonylethanol	IC50	23.3 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(3-methyl-2-pyridinyl)pyrimidin-2-yl]piperidin-4-yl]methanesulfonamide	IC50	24.4 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[4-[5-chloro-4-(3-methyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]-2,2-dimethylpropan-1-one	IC50	25.5 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[5-chloro-4-(3-methyl-2-pyridinyl)-2-pyridinyl]-N-[[4-(cyclopropylmethyl)-5-oxomorpholin-2-yl]methyl]piperidine-4-carboxamide	IC50	25.5 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[5-chloro-4-(3-methyl-2-pyridinyl)-2-pyridinyl]-N-[1-(hydroxymethyl)cyclopentyl]piperidine-4-carboxamide	IC50	25.8 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
[1-(5-chloro-6-pyridin-2-yl-2-pyridinyl)piperidin-4-yl]methanesulfonamide	IC50	26.3 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-(5-chloro-6-pyridin-2-yl-2-pyridinyl)piperidin-4-yl]-2-methoxyethanesulfonamide	IC50	26.7 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[5-chloro-4-(3-methyl-2-pyridinyl)-2-pyridinyl]-N-(2-hydroxycyclohexyl)piperidine-4-carboxamide	IC50	28.3 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[5-chloro-4-(3-methyl-2-pyridinyl)-2-pyridinyl]-N-[4-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide	IC50	28.5 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]-4-(2-methoxyethylsulfonyl)piperazine	IC50	29.2 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-6-(5-fluoro-3-methyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	29.2 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(5-fluoro-3-methyl-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]-3-methylsulfonylpropanamide	IC50	29.8 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
5-chloro-4-(3-methyl-2-pyridinyl)-2-[4-(methylsulfonylmethyl)piperidin-1-yl]pyrimidine	IC50	30 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-(5-chloro-6-pyridin-2-yl-2-pyridinyl)piperidin-4-yl]-3-hydroxy-3-methylbutanamide	IC50	30.5 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-(5-chloro-6-pyridin-2-yl-2-pyridinyl)piperidin-4-yl]-3-methylsulfonylpropanamide	IC50	31.3 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(3-chloro-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	32.1 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
1-[5-chloro-4-(3-methyl-2-pyridinyl)-2-pyridinyl]-N-[(1R,2R)-2-hydroxycyclohexyl]piperidine-4-carboxamide	IC50	32.6 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators
N-[1-[5-chloro-4-(5-chloro-2-pyridinyl)-2-pyridinyl]piperidin-4-yl]methanesulfonamide	IC50	32.9 nM	US-9056865: Pyridine-2-derivatives as smoothened receptor modulators

ChEMBL bioactivities

886 potent at pChembl≥5 of 892 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.10	IC50	0.08	nM	CHEMBL4632769
9.70	IC50	0.2	nM	CHEMBL4637222
9.40	IC50	0.4	nM	VISMODEGIB
9.40	IC50	0.4	nM	CHEMBL1083915
9.30	EC50	0.5	nM	CHEMBL4632769
9.15	IC50	0.7	nM	CHEMBL1086467
9.00	IC50	1	nM	CHEMBL1209455
8.85	IC50	1.4	nM	PATIDEGIB
8.82	EC50	1.5	nM	CHEMBL4637222
8.70	EC50	2	nM	VISMODEGIB
8.66	IC50	2.2	nM	CHEMBL1084835
8.64	IC50	2.3	nM	CHEMBL1084730
8.62	IC50	2.4	nM	CHEMBL2059863
8.62	IC50	2.4	nM	CHEMBL2059865
8.60	IC50	2.5	nM	SONIDEGIB PHOSPHATE
8.59	IC50	2.6	nM	CHEMBL2059864
8.57	IC50	2.7	nM	CHEMBL1084734
8.55	IC50	2.8	nM	CHEMBL1084738
8.52	EC50	3	nM	VISMODEGIB
8.52	IC50	3	nM	CHEMBL1823863
8.51	IC50	3.1	nM	CHEMBL1084736
8.49	IC50	3.2	nM	CHEMBL1083284
8.48	IC50	3.3	nM	CHEMBL1209189
8.44	IC50	3.6	nM	CHEMBL1083914
8.41	IC50	3.9	nM	CHEMBL4441310
8.40	IC50	4	nM	CHEMBL2160067
8.40	IC50	4	nM	CHEMBL1813106
8.38	IC50	4.17	nM	TALADEGIB
8.36	IC50	4.4	nM	CHEMBL1085503
8.32	IC50	4.8	nM	CHEMBL1209190
8.32	IC50	4.74	nM	CHEMBL515916
8.30	IC50	5	nM	CHEMBL2031290
8.30	IC50	5	nM	CHEMBL2059859
8.30	IC50	5	nM	CHEMBL2059866
8.30	IC50	5	nM	CHEMBL561533
8.30	IC50	5	nM	CHEMBL1209156
8.30	IC50	5	nM	CHEMBL1813106
8.30	IC50	5	nM	CHEMBL1813107
8.30	IC50	5	nM	CHEMBL1822467
8.29	IC50	5.1	nM	VISMODEGIB
8.28	IC50	5.2	nM	CHEMBL1084737
8.28	IC50	5.2	nM	CHEMBL1084837
8.28	IC50	5.3	nM	CHEMBL1086045
8.28	IC50	5.3	nM	CHEMBL1086048
8.28	IC50	5.3	nM	CHEMBL1084737
8.25	IC50	5.6	nM	CHEMBL3604610
8.24	IC50	5.8	nM	CHEMBL3186656
8.24	IC50	5.8	nM	CHEMBL1209454
8.22	Ki	6	nM	SONIDEGIB
8.22	IC50	6	nM	VISMODEGIB

PubChem BioAssay actives

659 with measured affinity, of 1091 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
N-[5-(1H-imidazol-2-yl)-2,4-dimethylphenyl]-4-(pyridin-2-ylmethoxy)benzamide	1650665: Inhibition of SMO-mediated hedgehog signalling pathway in human HPEM cells by luciferase reporter gene assay	ic50	0.0001	uM
N-[2,4-dimethyl-5-(1-methylimidazol-4-yl)phenyl]-4-(pyridin-2-ylmethoxy)benzamide	1650665: Inhibition of SMO-mediated hedgehog signalling pathway in human HPEM cells by luciferase reporter gene assay	ic50	0.0002	uM
Vismodegib	1650665: Inhibition of SMO-mediated hedgehog signalling pathway in human HPEM cells by luciferase reporter gene assay	ic50	0.0004	uM
[(3R)-3-methyl-4-[4-(4-methylphenyl)phthalazin-1-yl]piperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0004	uM
[(3R)-4-[4-(4-chlorophenyl)phthalazin-1-yl]-3-methylpiperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0007	uM
[(3R)-3-methyl-4-[1-[4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyridazin-4-yl]piperazin-1-yl]-phenylmethanone	493691: Antagonist activity at human Smo receptor in HEPM cells assessed as inhibition of Gli expression after 24 hrs by quantigene assay	ic50	0.0010	uM
N-[(3R,3’R,3’aS,4aR,6’S,6aR,6bS,7’aR,9S,12aS,12bS)-3’,6’,11,12b-tetramethylspiro[1,2,3,4,4a,5,6,6a,6b,7,8,10,12,12a-tetradecahydronaphtho[2,1-a]azulene-9,2’-3a,4,5,6,7,7a-hexahydro-3H-furo[3,2-b]pyridine]-3-yl]methanesulfonamide	420893: Inhibition of human recombinant SMO expressed in mouse C3H10T1/2 cells assessed as inhibition of association of BODIPY-cyclopamine	ic50	0.0014	uM
[(3R)-3-methyl-4-(4-phenylphthalazin-1-yl)piperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0022	uM
[(3R)-4-[4-(4-cyclopropylphenyl)phthalazin-1-yl]-3-methylpiperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0023	uM
N-[5-(1H-imidazol-2-yl)-2-methylphenyl]-4-(pyridin-2-ylmethoxy)benzamide	1650665: Inhibition of SMO-mediated hedgehog signalling pathway in human HPEM cells by luciferase reporter gene assay	ic50	0.0024	uM
N-[2-methyl-5-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl]-4-(pyridin-2-ylmethoxy)benzamide	672351: Inhibition of Smo expressed in mouse NIH/3T3 cells after 20 hrs by Gli reporter gene assay	ic50	0.0024	uM
Sonidegib Phosphate	2131630: Antagonist activity at human SMO	ic50	0.0025	uM
N-[2-methyl-5-(5-methyl-1H-imidazol-2-yl)phenyl]-4-(pyridin-2-ylmethoxy)benzamide	672351: Inhibition of Smo expressed in mouse NIH/3T3 cells after 20 hrs by Gli reporter gene assay	ic50	0.0026	uM
[(3R)-4-[4-[4-(hydroxymethyl)phenyl]phthalazin-1-yl]-3-methylpiperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0027	uM
[(3R)-3-methyl-4-[4-[4-(trifluoromethyl)phenyl]phthalazin-1-yl]piperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0028	uM
N-cyclohexyl-4-[3-(1-methylbenzimidazol-2-yl)-1,2,4-oxadiazol-5-yl]piperazine-1-carboxamide	616732: Displacement of Bodipy-labelled cyclopamine from Smo expressed in COS-1 cells in presence of 2% FBS after 4 to 6 hrs by FACS flow cytometric analysis	ic50	0.0030	uM
4-[4-[(2R)-4-benzoyl-2-methylpiperazin-1-yl]phthalazin-1-yl]benzonitrile	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0031	uM
[(2S)-2-methyl-4-[4-(4-methylphenyl)phthalazin-1-yl]piperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0032	uM
[4-[4-[(2R)-4-benzoyl-2-methylpiperazin-1-yl]phthalazin-1-yl]phenyl] acetate	493691: Antagonist activity at human Smo receptor in HEPM cells assessed as inhibition of Gli expression after 24 hrs by quantigene assay	ic50	0.0033	uM
[(2S)-2-methyl-4-[4-[4-(trifluoromethyl)phenyl]phthalazin-1-yl]piperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0036	uM
N-(2-methylcyclohexyl)-1-[5-[5-[[(5-methyl-2-pyridinyl)amino]methyl]pyrazol-1-yl]-1,3,4-thiadiazol-2-yl]piperidine-4-carboxamide	1595365: Displacement of BODIPY-Cyclopamine from human HA-tagged Smo receptor expressed in human U2OS cells at 1 to 10000 nM incubated for 2 hrs by DAPI staining based fluorescence microscopic method	ic50	0.0039	uM
N-[4-chloro-3-(5-phenyl-1H-imidazol-2-yl)phenyl]-2-[(2R)-2-methylmorpholin-4-yl]-1,6-naphthyridin-5-amine	693852: Antagonist activity at human Smo expressed in CHO cells assessed as inhibition of BODIPY-cyclopamine binding after 4 hrs by fluorescence assay	ic50	0.0040	uM
(8aS)-N-[2-(3-chlorophenyl)-3-pyridinyl]-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazine-7-carboxamide	612237: Displacement of BODIPY-cyclopamine from human Smo expressed in HEK293 cells in presence of 2% fetal calf serum	ic50	0.0040	uM
4-fluoro-N-methyl-N-[1-[4-(2-methylpyrazol-3-yl)phthalazin-1-yl]piperidin-4-yl]-2-(trifluoromethyl)benzamide	1667114: Inhibition of SMO D473H mutant receptor (unknown origin) assessed as inhibition of SAG-induced Hh signaling pathway by Gli luciferase reporter cell-based assay	ic50	0.0042	uM
[4-[4-(4-methylphenyl)phthalazin-1-yl]piperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0044	uM
(E)-N-(4-benzylpiperazin-1-yl)-1-(3,5-dimethyl-1-phenylpyrazol-4-yl)methanimine	494009: Inhibition of Smoothened transfected in HEK293 cells by transient transfection cell-based assay	ic50	0.0047	uM
2-[4-[4-[(2R)-4-benzoyl-2-methylpiperazin-1-yl]phthalazin-1-yl]phenyl]acetamide	493691: Antagonist activity at human Smo receptor in HEPM cells assessed as inhibition of Gli expression after 24 hrs by quantigene assay	ic50	0.0048	uM
3,4,5-trimethoxy-N-[N’-[4-methyl-3-[(4-phenylbenzoyl)amino]phenyl]carbamimidoyl]benzamide	661558: Displacement of BODIPY-labelled cyclopamine from human Smo receptor expressed in HEK293 cells after 2 hrs by fluorescence microscopy	ic50	0.0050	uM
N-[[1-(2-methoxyphenyl)indazol-5-yl]methyl]-2-propylpentanamide	430724: Inhibition of BODIPY-cyclopamine to Smo in human HEK293 Flag-Smo cells in presence of 2% FCS	ic50	0.0050	uM
1-[[1-(4-fluorophenyl)-5-methylpyrazol-4-yl]methyl]-4-(3-methoxyphenyl)piperazine	494010: Inhibition of Smoothened transfected in HEK293 cells by binding assay	ic50	0.0050	uM
4-[3-(1-methylbenzimidazol-2-yl)-1,2,4-oxadiazol-5-yl]-N-[(1-piperidin-1-ylcyclopentyl)methyl]piperazine-1-carboxamide	616569: Displacement of BODIPY-cyclopamine from Smo expressed in COS-1 cells after 4 to 6 hrs by Flow Cytometry analysis in presence of 2% fetal calf serum	ic50	0.0050	uM
(8aS)-N-[2-(3-cyanophenyl)-3-pyridinyl]-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazine-7-carboxamide	612236: Antagonist activity at smoothened expressed in mouse Shh Light2 cells assessed as inhibition of purmorphamine- induced Gli-dependent luciferase gene expression	ic50	0.0050	uM
N-[5-(1H-benzimidazol-2-yl)-2-methylphenyl]-4-(pyridin-2-ylmethoxy)benzamide	672351: Inhibition of Smo expressed in mouse NIH/3T3 cells after 20 hrs by Gli reporter gene assay	ic50	0.0050	uM
N-[2-methyl-5-(1-methylimidazol-4-yl)phenyl]-4-(pyridin-2-ylmethoxy)benzamide	672351: Inhibition of Smo expressed in mouse NIH/3T3 cells after 20 hrs by Gli reporter gene assay	ic50	0.0050	uM
[4-[4-(4-chlorophenyl)phthalazin-1-yl]piperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0052	uM
[(3R)-4-[4-[4-(dimethylamino)phenyl]phthalazin-1-yl]-3-methylpiperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0052	uM
[(2S)-2-methyl-4-(4-phenylphthalazin-1-yl)piperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0053	uM
[(3S)-3-methyl-4-(4-phenylphthalazin-1-yl)piperazin-1-yl]-phenylmethanone	493691: Antagonist activity at human Smo receptor in HEPM cells assessed as inhibition of Gli expression after 24 hrs by quantigene assay	ic50	0.0053	uM
N-[5-(2-acetamido-1,3-benzothiazol-6-yl)-2-chloro-3-pyridinyl]benzamide	1239806: Inhibition of human Smo expressed in human U2OS cells assessed as reduction in BODIPY-cyclopamine fluorescence signaling by competitive displacement assay	ic50	0.0056	uM
[(3R)-3-methyl-4-(1-phenylpyrido[3,4-d]pyridazin-4-yl)piperazin-1-yl]-phenylmethanone	493691: Antagonist activity at human Smo receptor in HEPM cells assessed as inhibition of Gli expression after 24 hrs by quantigene assay	ic50	0.0058	uM
1-[4-[5-chloro-4-(3,5-dimethyl-2-pyridinyl)-2-pyridinyl]piperazin-1-yl]-3-methylsulfonylpropan-1-one	1846003: Binding affinity to human SMO (181 to 787 residues) expressed in human HEK293 cells assessed as radioactivity incubated for 2 hrs in presence of H3-labeled smo antagonist by ligand-displacement assay	ic50	0.0058	uM
Sonidegib	695425: Displacement of [3H]cyclopamine from wild type Smo expressed in U2OS cells after 2 hrs by scintillation counting	ki	0.0060	uM
N-[5-(1,5-dimethylimidazol-2-yl)-2-methylphenyl]-4-(pyridin-2-ylmethoxy)benzamide	672351: Inhibition of Smo expressed in mouse NIH/3T3 cells after 20 hrs by Gli reporter gene assay	ic50	0.0060	uM
(8aS)-N-[2-(3-fluorophenyl)pyrazol-3-yl]-1,3-dioxo-2-[(1S,2R)-2-phenylcyclopropyl]-5,6,8,8a-tetrahydroimidazo[1,5-a]pyrazine-7-carboxamide	612236: Antagonist activity at smoothened expressed in mouse Shh Light2 cells assessed as inhibition of purmorphamine- induced Gli-dependent luciferase gene expression	ic50	0.0060	uM
2-chloro-N-[4-(3-phenylphenyl)phenyl]benzamide	617684: Antagonist activity at human SMO expressed in HEPM cells assessed as reduction of GLI expression after 24 hrs by Quantigene assay	ic50	0.0064	uM
3-methyl-N-[(2S)-2-(thiophen-2-ylmethylamino)-2,3-dihydro-1H-inden-5-yl]-2-[4-(trifluoromethyl)phenyl]benzamide	392425: Antagonist activity at human Smo receptor expressed in CHO cells by [3H]Hh-Ag binding assay	ic50	0.0070	uM
3-methyl-N-[(2S)-2-[(4-methyl-1,3-thiazol-2-yl)methylamino]-2,3-dihydro-1H-inden-5-yl]-2-[4-(trifluoromethyl)phenyl]benzamide	392425: Antagonist activity at human Smo receptor expressed in CHO cells by [3H]Hh-Ag binding assay	ic50	0.0070	uM
[(2S)-4-[4-(4-chlorophenyl)phthalazin-1-yl]-2-methylpiperazin-1-yl]-phenylmethanone	483016: Inhibition of human SMO expressed in HEPM cells	ic50	0.0070	uM
N-(4,4-difluorocyclohexyl)-4-[3-(1-methylbenzimidazol-2-yl)-1,2,4-oxadiazol-5-yl]piperazine-1-carboxamide	616732: Displacement of Bodipy-labelled cyclopamine from Smo expressed in COS-1 cells in presence of 2% FBS after 4 to 6 hrs by FACS flow cytometric analysis	ic50	0.0070	uM
N-[2-methyl-5-(2-methyl-1H-imidazol-5-yl)phenyl]-4-(pyridin-2-ylmethoxy)benzamide	672351: Inhibition of Smo expressed in mouse NIH/3T3 cells after 20 hrs by Gli reporter gene assay	ic50	0.0070	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects expression, decreases methylation, affects cotreatment, increases expression	7
Resveratrol	decreases expression	3
salinomycin	decreases expression	2
Sunitinib	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Fluorouracil	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
cyclopamine	increases expression, decreases reaction	1
napabucasin	decreases expression	1
bisphenol A	affects expression	1
mono-(2-ethylhexyl)phthalate	affects cotreatment, increases expression, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	increases expression	1
nickel monoxide	decreases reaction, increases expression	1
evodiamine	increases expression	1
goralatide	affects cotreatment, decreases reaction, increases expression	1
baohuoside I	decreases reaction, increases expression, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
HhAntag691	decreases expression	1
jinfukang	increases expression, increases reaction	1
GANT 61	decreases reaction, increases expression	1
4-acetylantroquinonol B	decreases expression	1
Agent Orange	decreases methylation, increases abundance	1
Temozolomide	increases expression	1
Arsenic Trioxide	decreases activity	1
Leflunomide	decreases expression	1

ChEMBL screening assays

131 unique, capped per target: 111 binding, 20 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1029071	Binding	Antagonist activity at human Smo receptor expressed in CHO cells by [3H]Hh-Ag binding assay	Identification and structure-activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signaling pathway. — Bioorg Med Chem Lett
CHEMBL1212595	Functional	Antagonist activity at human Smo receptor in HEPM cells assessed as inhibition of Gli expression after 24 hrs by quantigene assay	Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines. — Bioorg Med Chem Lett

Cellosaurus cell lines

13 cell lines: 7 cancer cell line, 3 spontaneously immortalized cell line, 2 transformed cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B3HS	Abcam HEK293T SMO KO	Transformed cell line	Female
CVCL_B6PU	Powder	Cancer cell line	Female
CVCL_B8PS	Abcam HCT 116 SMO KO	Cancer cell line	Male
CVCL_B9S8	Abcam A-549 SMO KO	Cancer cell line	Male
CVCL_D8AZ	Ubigene A-549 SMO KO	Cancer cell line	Male
CVCL_D8VP	Ubigene HCT 116 SMO KO	Cancer cell line	Male
CVCL_D9SD	Ubigene HEK293 SMO KO	Transformed cell line	Female
CVCL_E7X5	NIH-3T3-Flag-Smo 1.1	Spontaneously immortalized cell line	Male
CVCL_E7X6	NIH-3T3-Flag-Smo 1.7	Spontaneously immortalized cell line	Male
CVCL_E7X7	NIH-3T3-eGFP-Smo	Spontaneously immortalized cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02875314	PHASE4	ACTIVE_NOT_RECRUITING	HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors
NCT04081701	PHASE4	RECRUITING	68-Ga DOTATATE PET/MRI in the Diagnosis and Management of Somatostatin Receptor Positive CNS Tumors.
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT00085735	PHASE3	COMPLETED	Comparison of Radiation Therapy Regimens in Combination With Chemotherapy in Treating Young Patients With Newly Diagnosed Standard-Risk Medulloblastoma
NCT00336024	PHASE3	COMPLETED	Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma
NCT00392327	PHASE3	ACTIVE_NOT_RECRUITING	Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma/PNET
NCT01351870	PHASE3	COMPLETED	Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma (PNET4)
NCT07291102	PHASE3	NOT_YET_RECRUITING	Comparison of Neurocognitive Outcome in Two Standard Regimen for Treatment of Low-risk Medulloblastoma
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00031590	PHASE2	TERMINATED	Low-Dose Radiation and Combination Chemotherapy Following Surgery in Children With Newly Diagnosed Medulloblastoma
NCT00180791	PHASE2	UNKNOWN	High Risk Primitive Neuroectodermal (PNET) Brain Tumors in Childhood
NCT00180947	PHASE2	UNKNOWN	Study of Vinorelbine and Cyclofosfamide Among Patients With Refractory Tumours or in Relapse
NCT00404495	PHASE2	COMPLETED	Combination of Irinotecan and Temozolomide in Children With Brain Tumors.
NCT00407433	PHASE2	COMPLETED	Clinical Studies of Gemcitabine-Oxaliplatin
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NCT01217437	PHASE2	COMPLETED	Temozolomide and Irinotecan Hydrochloride With or Without Bevacizumab in Treating Young Patients With Recurrent or Refractory Medulloblastoma or CNS Primitive Neuroectodermal Tumors
NCT01326104	PHASE2	COMPLETED	Vaccine Immunotherapy for Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor
NCT01356290	PHASE2	RECRUITING	Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors
NCT01542736	PHASE2	COMPLETED	Concurrent Carboplatin and Reduced Dose Craniospinal Radiation for Medulloblastoma and Primitive Neuroectodermal Tumor (PNET)
NCT01708174	PHASE2	COMPLETED	A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB)
NCT01857453	PHASE2	UNKNOWN	Interest of a Dose Decrease for Radiotherapy Associated With Chemotherapy for Treatment of Standard Risk Adult Medulloblastomas
NCT01878617	PHASE2	ACTIVE_NOT_RECRUITING	A Clinical and Molecular Risk-Directed Therapy for Newly Diagnosed Medulloblastoma
NCT02017964	PHASE2	COMPLETED	Combination Chemotherapy in Treating Younger Patients With Newly Diagnosed, Non-metastatic Desmoplastic Medulloblastoma
NCT02441062	PHASE2	COMPLETED	Impact of Ga-68 DOTATOC PET-CT Imaging in Management of Neuroendocrine Tumors
NCT02624388	PHASE2	TERMINATED	Study of Genistein in Pediatric Oncology Patients (UVA-Gen001)
NCT02681705	PHASE2	UNKNOWN	Radiation Therapy and Combination Chemotherapy for Medulloblastoma
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT02724579	PHASE2	ACTIVE_NOT_RECRUITING	Reduced Craniospinal Radiation Therapy and Chemotherapy in Treating Younger Patients With Newly Diagnosed WNT-Driven Medulloblastoma
NCT03013387	PHASE2	WITHDRAWN	Dosimetry Guided PRRT With 90Y-DOTATOC
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03173950	PHASE2	COMPLETED	Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)