TLL2

Summary

TLL2 (tolloid like 2, HGNC:11844) is a protein-coding gene on chromosome 10q24.1, encoding Tolloid-like protein 2 (Q9Y6L7). Protease which specifically processes pro-lysyl oxidase.

This gene encodes an astacin-like zinc-dependent metalloprotease and is a subfamily member of the metzincin family. Unlike other family members, a similar protein in mice does not cleave procollagen C-propeptides or chordin.

Source: NCBI Gene 7093 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 197 total
• Druggable target: yes
• MANE Select transcript: NM_012465

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11844
Approved symbol	TLL2
Name	tolloid like 2
Location	10q24.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000095587
Ensembl biotype	protein_coding
OMIM	606743
Entrez	7093

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000357947, ENST00000469598, ENST00000506028, ENST00000881335, ENST00000881336, ENST00000929059

RefSeq mRNA: 1 — MANE Select: NM_012465 NM_012465

CCDS: CCDS7449

Canonical transcript exons

ENST00000357947 — 21 exons

Exon	Start	End
ENSE00000717568	96370065	96370315
ENSE00000717579	96373596	96373809
ENSE00000717582	96376692	96376819
ENSE00000717588	96378967	96379092
ENSE00000717597	96384587	96384767
ENSE00000717600	96386055	96386215
ENSE00000717612	96386953	96387078
ENSE00000717628	96395187	96395382
ENSE00000811057	96432807	96432962
ENSE00001224361	96364608	96368222
ENSE00001224366	96513511	96513926
ENSE00003567488	96397186	96397302
ENSE00003573137	96395875	96396020
ENSE00003590860	96405232	96405334
ENSE00003593650	96480349	96480459
ENSE00003619512	96410359	96410474
ENSE00003622871	96420956	96421061
ENSE00003672050	96428631	96428748
ENSE00003672919	96422549	96422727
ENSE00003679887	96446091	96446168
ENSE00003681074	96413192	96413316

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 92.46.

FANTOM5 (CAGE): breadth broad, TPM avg 0.8388 / max 40.8465, expressed in 389 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110866	0.6606	333
110867	0.1782	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	92.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.77	gold quality
apex of heart	UBERON:0002098	78.52	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.40	gold quality
heart left ventricle	UBERON:0002084	74.66	gold quality
cardiac ventricle	UBERON:0002082	74.64	gold quality
Brodmann (1909) area 23	UBERON:0013554	73.98	gold quality
heart right ventricle	UBERON:0002080	73.62	gold quality
triceps brachii	UBERON:0001509	73.49	gold quality
gluteal muscle	UBERON:0002000	73.45	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	72.93	gold quality
middle temporal gyrus	UBERON:0002771	72.63	silver quality
spinal cord	UBERON:0002240	70.83	gold quality
hindlimb stylopod muscle	UBERON:0004252	70.79	gold quality
diaphragm	UBERON:0001103	69.77	gold quality
heart	UBERON:0000948	68.48	gold quality
primary visual cortex	UBERON:0002436	67.21	gold quality
prefrontal cortex	UBERON:0000451	67.12	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	67.01	gold quality
endothelial cell	CL:0000115	66.77	gold quality
vastus lateralis	UBERON:0001379	66.14	gold quality
quadriceps femoris	UBERON:0001377	66.05	gold quality
tongue squamous epithelium	UBERON:0006919	65.48	gold quality
cardiac atrium	UBERON:0002081	65.26	gold quality
right atrium auricular region	UBERON:0006631	65.18	gold quality
cardiac muscle of right atrium	UBERON:0003379	64.65	gold quality
islet of Langerhans	UBERON:0000006	64.62	gold quality
Brodmann (1909) area 9	UBERON:0013540	63.71	gold quality
occipital lobe	UBERON:0002021	63.67	gold quality
type B pancreatic cell	CL:0000169	63.45	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

145 targeting TLL2, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786

Literature-anchored findings (GeneRIF, showing 4)

• The crystal structures of the protease domains of human BMP-1 and the closely related Tolloid-like protease 1 (TLL-1), are reported. (PMID:18824173)
• By means of a cross-species comparative genetic strategy we describe an association for TLL2 with bipolar disorder. (PMID:23777486)
• Findings suggest that these MMP16 rs10090371, ADAMTS3 rs788935, TLL2 rs10882807 and MMP9 rs3918251 may be promising prognostic biomarkers for cutaneous melanoma specific survival (CMSS). (PMID:28796414)
• genomic analysis identified compound heterozygous mutations at TLL2 on the male patient’s genome, and compound heterozygous mutations at VPS13A and the de novo mutation at AGAP5 on female patient’s genome (PMID:31888525)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Tll2	ENSMUSG00000025013
rattus_norvegicus	Tll2	ENSRNOG00000013519

Paralogs (35): NRXN3 (ENSG00000021645), TLL1 (ENSG00000038295), CP (ENSG00000047457), DCBLD2 (ENSG00000057019), HEPH (ENSG00000089472), NRP1 (ENSG00000099250), PCOLCE (ENSG00000106333), CNTNAP3 (ENSG00000106714), CUBN (ENSG00000107611), CNTNAP1 (ENSG00000108797), NRXN2 (ENSG00000110076), MEP1A (ENSG00000112818), NRP2 (ENSG00000118257), CUZD1 (ENSG00000138161), MFGE8 (ENSG00000140545), MEP1B (ENSG00000141434), PDGFC (ENSG00000145431), CNTNAP4 (ENSG00000152910), CNTNAP3B (ENSG00000154529), CNTNAP5 (ENSG00000155052), CDCP2 (ENSG00000157211), PCOLCE2 (ENSG00000163710), EDIL3 (ENSG00000164176), NETO1 (ENSG00000166342), BMP1 (ENSG00000168487), PDGFD (ENSG00000170962), NETO2 (ENSG00000171208), CNTNAP2 (ENSG00000174469), NRXN1 (ENSG00000179915), HEPHL1 (ENSG00000181333), F8 (ENSG00000185010), ASTL (ENSG00000188886), F5 (ENSG00000198734), MFRP (ENSG00000235718), CNTNAP3C (ENSG00000283378)

Protein

Protein identifiers

Tolloid-like protein 2 — Q9Y6L7 (reviewed: Q9Y6L7)

All UniProt accessions (1): Q9Y6L7

UniProt curated annotations — full annotation on UniProt →

Function. Protease which specifically processes pro-lysyl oxidase. Required for the embryonic development. Predominant protease, which in the development, influences dorsal-ventral patterning and skeletogenesis.

Subcellular location. Secreted.

Cofactor. Binds 1 zinc ion per subunit.

RefSeq proteins (1): NP_036597* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR000859	CUB_dom	Domain
IPR001506	Peptidase_M12A	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR006026	Peptidase_Metallo	Domain
IPR015446	BMP_1/tolloid-like	Family
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR024079	MetalloPept_cat_dom_sf	Homologous_superfamily
IPR034036	ZnMP_TLD/BMP1	Domain
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain

Pfam: PF00431, PF01400, PF07645, PF14670

UniProt features (47 total): disulfide bond 19, domain 8, glycosylation site 5, binding site 3, region of interest 2, compositionally biased region 2, modified residue 2, sequence conflict 2, signal peptide 1, propeptide 1, active site 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6L7-F1	81.98	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.

Catalytic / active sites (1): 243

Ligand- & substrate-binding residues (3): 242; 246; 252

Post-translational modifications (2): 963, 966

Disulfide bonds (19): 192–348, 212–234, 214–215, 351–377, 404–426, 464–490, 517–539, 580–592, 588–601, 603–616, 620–646, 673–695, 736–747, 743–756, 758–771, 776–802, 829–851, 889–919, 946–968

Glycosylation sites (5): 171, 361, 392, 628, 805

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-1650814	Collagen biosynthesis and modifying enzymes
R-HSA-2214320	Anchoring fibril formation
R-HSA-2243919	Crosslinking of collagen fibrils

MSigDB gene sets: 168 (showing top): RRAGTTGT_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_MUSCLE_TISSUE_DEVELOPMENT, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOMF_METALLOPEPTIDASE_ACTIVITY, BROWNE_HCMV_INFECTION_8HR_UP, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_GROWTH, TGACCTY_ERR1_Q2, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, GOBP_NEGATIVE_REGULATION_OF_DEVELOPMENTAL_GROWTH, TCF4_Q5, GGGCATT_MIR365, GOBP_PROTEIN_MATURATION

GO Biological Process (6): dorsal/ventral pattern formation (GO:0009953), protein processing (GO:0016485), cell differentiation (GO:0030154), collagen fibril organization (GO:0030199), negative regulation of skeletal muscle tissue growth (GO:0048632), proteolysis (GO:0006508)

GO Molecular Function (8): metalloendopeptidase activity (GO:0004222), serine-type endopeptidase activity (GO:0004252), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Assembly of collagen fibrils and other multimeric structures	2
Extracellular matrix organization	1
Collagen formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endopeptidase activity	2
regionalization	1
proteolysis	1
protein maturation	1
cellular developmental process	1
extracellular matrix organization	1
skeletal muscle tissue growth	1
regulation of skeletal muscle tissue growth	1
negative regulation of developmental growth	1
protein metabolic process	1
metallopeptidase activity	1
serine-type peptidase activity	1
metal ion binding	1
transition metal ion binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

448 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TLL2	CHRD	Q9H2X0	875
TLL2	LAMA3	Q16787	639
TLL2	LAMC2	Q13753	589
TLL2	LAMA4	Q16363	549
TLL2	CSH1	P01243	546
TLL2	CSH1	P01243	541
TLL2	MSTN	O14793	487
TLL2	CXorf38	Q8TB03	419
TLL2	AGAP5	A6NIR3	401
TLL2	PRL	P01236	368
TLL2	ZNF284	Q2VY69	361
TLL2	SFTPC	P11686	342
TLL2	FURIN	P09958	332
TLL2	ACSM6	Q6P461	313
TLL2	EBLN1	P0CF75	311

IntAct

20 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
BMP1	TLL1	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
OS9	GXYLT2	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350
TMEM87A	POTEF	psi-mi:“MI:0914”(association)	0.350
DNAJB9	POTEF	psi-mi:“MI:0914”(association)	0.350
MFAP4	QSOX1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
SDF2L1	MANBA	psi-mi:“MI:0914”(association)	0.350
OIT3	WNT10B	psi-mi:“MI:0914”(association)	0.350
SLURP1	MAN2B1	psi-mi:“MI:0914”(association)	0.350
PAEP	EIF3H	psi-mi:“MI:0914”(association)	0.350
CRISP2	LRP5	psi-mi:“MI:0914”(association)	0.350
C1orf54	QSOX1	psi-mi:“MI:0914”(association)	0.350
C1QTNF9B	DNASE2	psi-mi:“MI:0914”(association)	0.350
PATE1	AGRN	psi-mi:“MI:0914”(association)	0.350

BioGRID (17): TLL2 (Affinity Capture-MS), TLL2 (Synthetic Lethality), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS), TLL2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0C5PRQ1, A0FKN6, A8Q2D1, D5FM34, D5FM37, K7Z9Q9, O17264, O35548, O43897, O54732, O57460, P13497, P25723, P50281, P51511, P51512, P53690, P55114, P98060, P98069, P98070, Q10739, Q11005, Q18206, Q19204, Q20459, Q20942, Q20958, Q21178, Q21252, Q22396, Q22710, Q5RES1, Q5W7F4, Q61EX6, Q62381, Q7JLI1, Q7Z0M7, Q8JI28, Q93243

Diamond homologs: A0A0C5PRQ1, A0FKN6, A8Q2D1, C9D7R2, C9D7R3, D2KBH9, D5FM34, D5FM37, D5FM38, K7Z9Q9, O16977, O17264, O43897, O57382, O57460, O62243, P07584, P0DM61, P0DM62, P13497, P28825, P28826, P31579, P31580, P31581, P42674, P55112, P55113, P55114, P55115, P84748, P91137, P98060, P98061, P98063, P98068, P98069, P98070, Q16819, Q16820

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	173
Likely benign	6
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

4085 predictions. Top by Δscore:

Variant	Effect	Δscore
10:96368110:T:TA	donor_gain	1.0000
10:96370058:GACTT:G	donor_loss	1.0000
10:96370059:ACTTA:A	donor_loss	1.0000
10:96370060:CTTA:C	donor_loss	1.0000
10:96370061:TTAC:T	donor_loss	1.0000
10:96370062:TACC:T	donor_loss	1.0000
10:96370063:A:AC	donor_gain	1.0000
10:96370063:A:AT	donor_loss	1.0000
10:96370063:ACC:A	donor_gain	1.0000
10:96370064:C:CC	donor_gain	1.0000
10:96370064:C:CT	donor_loss	1.0000
10:96370064:CCC:C	donor_gain	1.0000
10:96370312:CACT:C	acceptor_gain	1.0000
10:96373663:A:AC	donor_gain	1.0000
10:96373664:C:CC	donor_gain	1.0000
10:96373664:CTG:C	donor_gain	1.0000
10:96378965:AC:A	donor_gain	1.0000
10:96378966:CC:C	donor_gain	1.0000
10:96378966:CCCT:C	donor_gain	1.0000
10:96384766:ACCTG:A	acceptor_loss	1.0000
10:96384768:C:A	acceptor_loss	1.0000
10:96384769:T:G	acceptor_loss	1.0000
10:96386053:A:AC	donor_gain	1.0000
10:96386054:C:CC	donor_gain	1.0000
10:96386056:T:TA	donor_gain	1.0000
10:96386065:T:TA	donor_gain	1.0000
10:96386080:TCAA:T	donor_gain	1.0000
10:96386213:CCA:C	acceptor_gain	1.0000
10:96386214:CAC:C	acceptor_gain	1.0000
10:96386216:C:CC	acceptor_gain	1.0000

AlphaMissense

6743 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:96422620:C:T	G249E	1.000
10:96422621:C:A	G249W	1.000
10:96422621:C:G	G249R	1.000
10:96422621:C:T	G249R	1.000
10:96422664:A:C	C234W	1.000
10:96422665:C:A	C234F	1.000
10:96422665:C:G	C234S	1.000
10:96422665:C:T	C234Y	1.000
10:96422666:A:G	C234R	1.000
10:96422666:A:T	C234S	1.000
10:96422683:A:T	I228K	1.000
10:96422721:G:C	C215W	1.000
10:96422722:C:T	C215Y	1.000
10:96422723:A:G	C215R	1.000
10:96422726:A:G	C214R	1.000
10:96428708:C:A	W187C	1.000
10:96428708:C:G	W187C	1.000
10:96428710:A:G	W187R	1.000
10:96428710:A:T	W187R	1.000
10:96432850:C:A	W159C	1.000
10:96432850:C:G	W159C	1.000
10:96395207:A:G	F569S	0.999
10:96395210:C:T	G568D	0.999
10:96395234:G:A	S560F	0.999
10:96395240:A:G	F558S	0.999
10:96395296:A:C	C539W	0.999
10:96395297:C:T	C539Y	0.999
10:96395348:A:G	L522P	0.999
10:96395354:T:A	D520V	0.999
10:96395363:C:T	C517Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000059509 (10:96475279 G>A), RS1000093979 (10:96477302 T>C), RS1000140959 (10:96413533 G>A), RS1000157768 (10:96487291 A>G), RS1000167485 (10:96500591 C>T), RS1000172189 (10:96413320 C>A,T), RS1000194175 (10:96445469 G>T), RS1000218579 (10:96458239 C>G), RS1000258284 (10:96384526 C>A,T), RS1000273722 (10:96365289 A>G), RS1000293512 (10:96464959 G>A), RS1000308447 (10:96406659 T>C), RS1000323887 (10:96465274 T>C), RS1000346496 (10:96383952 A>G), RS1000353332 (10:96451260 G>T)

Disease associations

OMIM: gene MIM:606743 | disease phenotypes: MIM:253300

GenCC curated gene-disease

Mondo (2): spinal muscular atrophy (MONDO:0001516), muscular atrophy (MONDO:0004323)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000246_12	Attention deficit hyperactivity disorder	2.000000e-06
GCST008508_6	Stress sensitivity (neuroticism score x major depressive disorder status interaction)	6.000000e-06
GCST010396_253	Gut microbiota (bacterial taxa, hurdle binary method)	2.000000e-07
GCST010485_6	Platelet reactivity in response to clopidogrel treatment	4.000000e-35

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009133	Muscular Atrophy	C10.597.613.612; C23.300.070.500; C23.888.592.608.612
D009134	Muscular Atrophy, Spinal	C10.228.854.468; C10.574.562.500; C10.668.467.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295995 (SINGLE PROTEIN)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.41	Ki	0.039	nM	CHEMBL4212386
9.59	Ki	0.26	nM	CHEMBL4214046
6.80	IC50	160	nM	CHEMBL4207308

PubChem BioAssay actives

3 with measured affinity, of 3 total; 3 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)-2-[[2-ethoxy-4-[5-[[[(2R)-2-[(1R)-1-[formyl(hydroxy)amino]propyl]heptanoyl]amino]methylcarbamoyl]furan-2-yl]benzoyl]amino]butanedioic acid	1385214: Binding affinity to TLL2 (unknown origin) using ((5-FAM)-ELIDQYDVQRDDSSDGSLED-K(5,6 TAMRA)-CONH2 as substrate incubated for 3.5 hrs followed by substrate addition by FRET assay	ki	<0.0001	uM
[3-ethoxy-5-[5-[[[(2R)-2-[(1R)-1-[formyl(hydroxy)amino]propyl]heptanoyl]amino]methylcarbamoyl]furan-2-yl]phenyl]phosphonic acid	1385214: Binding affinity to TLL2 (unknown origin) using ((5-FAM)-ELIDQYDVQRDDSSDGSLED-K(5,6 TAMRA)-CONH2 as substrate incubated for 3.5 hrs followed by substrate addition by FRET assay	ki	0.0003	uM
N-[[[(2R)-2-[(1R)-1-[formyl(hydroxy)amino]propyl]heptanoyl]amino]methyl]-5-phenylfuran-2-carboxamide	1385192: Inhibition of recombinant human N-terminal 6His-tagged TLL2 (26 to 1015 residues) expressed in CHO cells using ((5-FAM)-ELIDQYDVQRDDSSDGSLED-K(5,6 TAMRA)-CONH2) as substrate preincubated for 10 mins followed by substrate addition measured after 60 mins	ic50	0.1600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	increases expression	3
Valproic Acid	increases expression	3
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Tretinoin	increases expression	2
mivebresib	increases expression	1
methylmercuric chloride	increases expression	1
aflatoxin B2	decreases methylation	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, decreases expression, affects cotreatment	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
bisphenol S	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	increases expression	1
Endosulfan	increases expression	1
Estradiol	increases expression	1
Ethinyl Estradiol	increases expression	1
Progesterone	increases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Aflatoxin B1	increases methylation	1
Zinc Sulfate	increases expression	1
Okadaic Acid	increases expression	1
Genistein	increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4199882	Binding	Inhibition of recombinant human N-terminal 6His-tagged TLL2 (26 to 1015 residues) expressed in CHO cells using ((5-FAM)-ELIDQYDVQRDDSSDGSLED-K(5,6 TAMRA)-CONH2) as substrate preincubated for 10 mins followed by substrate addition measured a	Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1. — ACS Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01422200	PHASE4	COMPLETED	Flu Vaccine Study in Neuromuscular Patients 2011
NCT05232929	PHASE4	ACTIVE_NOT_RECRUITING	Long-term Follow-up Study of Risdiplam in Participants With Spinal Muscular Atrophy (SMA)
NCT05522361	PHASE4	ACTIVE_NOT_RECRUITING	Risdiplam in Patients With Spinal Muscular Atrophy Previously Treated With Nusinersen
NCT07448610	PHASE4	NOT_YET_RECRUITING	ASsessing The REAl-world Safety & Effectiveness of Spinal Muscular Atrophy Participants Treated With Intrathecal Onasemnogene Abeparvovec-brve (OAV101B) (ITVISMA®): A U.S. Pragmatic Multicenter Study (STREAM)
NCT00018356	PHASE4	COMPLETED	Physiologic Effects of PRMS & Testosterone in the Debilitated Elderly
NCT02568020	PHASE4	UNKNOWN	LPD+α-ketoacids on Autophagy and Improving Muscle Wasting in CKD
NCT01671384	PHASE3	UNKNOWN	Valproate and Levocarnitine in Children With Spinal Muscular Atrophy
NCT02193074	PHASE3	TERMINATED	A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy
NCT02292537	PHASE3	COMPLETED	A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Participants With Later-onset Spinal Muscular Atrophy (SMA)
NCT02594124	PHASE3	COMPLETED	A Study for Participants With Spinal Muscular Atrophy (SMA) Who Previously Participated in Nusinersen (ISIS 396443) Investigational Studies
NCT03505099	PHASE3	COMPLETED	Pre-Symptomatic Study of Intravenous Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2
NCT03837184	PHASE3	COMPLETED	Single-Dose Gene Replacement Therapy Using for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies
NCT04042025	PHASE3	ACTIVE_NOT_RECRUITING	Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi
NCT04851873	PHASE3	COMPLETED	Safety and Efficacy of Intravenous OAV101 (AVXS-101) in Pediatric Patients With Spinal Muscular Atrophy (SMA)
NCT05067790	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn About the Effect of Higher Doses of Nusinersen (BIIB058) Given as Injections to Participants With Spinal Muscular Atrophy (SMA) Who Were Previously Treated With Risdiplam (ASCEND)
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05335876	PHASE3	RECRUITING	Long-term Follow-up of Patients With Spinal Muscular Atrophy Treated With OAV101 in Clinical Trials
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05386680	PHASE3	COMPLETED	Phase IIIb, Open-label, Multi-center Study to Evaluate Safety, Tolerability and Efficacy of OAV101 Administered Intrathecally to Participants With SMA Who Discontinued Treatment With Nusinersen or Risdiplam
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT07265232	PHASE3	RECRUITING	Real World Clinical Effectiveness & Safety of Vesemnogene Lantuparvovec for Spinal Muscular Atrophy (SMA) in Low-middle Income Countries (LMIC).
NCT07444476	PHASE3	RECRUITING	A Study to Learn About Salanersen’s (BIIB115) Effects on Movement and Its Safety in Participants Aged 15 to 60 Years With Spinal Muscular Atrophy (SMA) Who Are Either New to SMA Treatment or Were Previously Treated With Risdiplam
NCT01373697	PHASE3	UNKNOWN	Study to Assess the Efficacy and Safety of Ibuprofen 50 mg/g Gel Compared to Profenid 25mg/g Gel
NCT01595581	PHASE3	COMPLETED	Testosterone Administration and ACL Reconstruction in Men
NCT03054168	PHASE3	UNKNOWN	Systemic Hormones and Muscle Protein Synthesis
NCT00004771	PHASE2	COMPLETED	Phase II Study of Leuprolide and Testosterone for Men With Kennedy’s Disease or Other Motor Neuron Disease
NCT00227266	PHASE2	COMPLETED	Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy
NCT00481013	PHASE2	COMPLETED	Valproic Acid in Ambulant Adults With Spinal Muscular Atrophy
NCT01028833	PHASE2	COMPLETED	Effects of Power Mobility on Young Children With Severe Motor Impairments
NCT01302600	PHASE2	COMPLETED	Safety and Efficacy of Olesoxime (TRO19622) in 3-25 Years SMA Patients.
NCT01839656	PHASE2	COMPLETED	A Study to Assess the Efficacy, Safety and Pharmacokinetics of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy (SMA)
NCT02386553	PHASE2	COMPLETED	A Study of Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
NCT02462759	PHASE2	TERMINATED	A Study to Assess the Safety and Tolerability of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA).
NCT02644668	PHASE2	COMPLETED	A Study of CK-2127107 in Patients With Spinal Muscular Atrophy
NCT02876094	PHASE2	TERMINATED	Effect of Low-Dose Celecoxib on SMN2 in Patients With Spinal Muscular Atrophy
NCT02941328	PHASE2	COMPLETED	SPACE Trial: Pyridostigmine vs Placebo in SMA Types 2, 3 and 4
NCT03032172	PHASE2	COMPLETED	A Study of Risdiplam (RO7034067) in Adult and Pediatric Participants With Spinal Muscular Atrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05794139	PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of NMD670 in Ambulatory Adult Patients With Type 3 Spinal Muscular Atrophy
NCT07047144	PHASE2	RECRUITING	A Study to Evaluate How Apitegromab Works in Subjects Who Are Less Than 2 Years Old and Have Spinal Muscular Atrophy