PDE12

Summary

PDE12 (phosphodiesterase 12, HGNC:25386) is a protein-coding gene on chromosome 3p14.3, encoding 2’,5’-phosphodiesterase 12 (Q6L8Q7). Enzyme that cleaves 2’,5’-phosphodiester bond linking adenosines of the 5’-triphosphorylated oligoadenylates, triphosphorylated oligoadenylates referred as 2-5A modulates the 2-5A system. It is a selective cancer dependency (DepMap: 22.8% of cell lines).

Enables poly(A)-specific ribonuclease activity. Involved in several processes, including cellular response to interferon-alpha; innate immune response; and mRNA catabolic process. Located in mitochondrial matrix.

Source: NCBI Gene 201626 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Strong, GenCC)
• Clinical variants (ClinVar): 59 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 22.8% of screened cell lines
• MANE Select transcript: NM_177966

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25386
Approved symbol	PDE12
Name	phosphodiesterase 12
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp667B1218, 2’-PDE, 3635
Ensembl gene	ENSG00000174840
Ensembl biotype	protein_coding
OMIM	616519
Entrez	201626

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding_CDS_not_defined, 4 protein_coding

ENST00000311180, ENST00000487257, ENST00000606192, ENST00000607297, ENST00000607782, ENST00000658756, ENST00000715954, ENST00000715955, ENST00000715956, ENST00000715957, ENST00000715958, ENST00000715959

RefSeq mRNA: 3 — MANE Select: NM_177966 NM_001322176, NM_001322177, NM_177966

CCDS: CCDS33772, CCDS82792

Canonical transcript exons

ENST00000311180 — 3 exons

Exon	Start	End
ENSE00001180922	57559310	57559388
ENSE00001401450	57559562	57566848
ENSE00001899217	57556274	57557687

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 92.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.2667 / max 117.4627, expressed in 1805 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36992	19.2667	1805

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of sigmoid colon	UBERON:0004993	92.33	gold quality
gingival epithelium	UBERON:0001949	92.21	gold quality
epithelium of nasopharynx	UBERON:0001951	91.71	gold quality
colonic mucosa	UBERON:0000317	91.50	gold quality
gingiva	UBERON:0001828	91.48	gold quality
oral cavity	UBERON:0000167	90.85	gold quality
pigmented layer of retina	UBERON:0001782	90.57	gold quality
retina	UBERON:0000966	90.55	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.33	gold quality
esophagus squamous epithelium	UBERON:0006920	90.19	gold quality
heart right ventricle	UBERON:0002080	89.92	gold quality
mucosa of paranasal sinus	UBERON:0005030	89.81	gold quality
biceps brachii	UBERON:0001507	89.80	gold quality
amniotic fluid	UBERON:0000173	89.69	gold quality
eye	UBERON:0000970	89.69	gold quality
germinal epithelium of ovary	UBERON:0001304	89.58	gold quality
superficial temporal artery	UBERON:0001614	89.45	gold quality
palpebral conjunctiva	UBERON:0001812	89.41	gold quality
cauda epididymis	UBERON:0004360	89.33	gold quality
trabecular bone tissue	UBERON:0002483	89.29	gold quality
mammalian vulva	UBERON:0000997	89.09	gold quality
jejunal mucosa	UBERON:0000399	88.97	gold quality
Brodmann (1909) area 23	UBERON:0013554	88.18	gold quality
seminal vesicle	UBERON:0000998	87.79	gold quality
vena cava	UBERON:0004087	87.39	silver quality
jejunum	UBERON:0002115	87.37	gold quality
cardia of stomach	UBERON:0001162	87.30	gold quality
superior surface of tongue	UBERON:0007371	87.10	gold quality
endothelial cell	CL:0000115	87.04	gold quality
corpus epididymis	UBERON:0004359	87.03	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-CURD-10	no	455.57
E-ANND-3	no	5.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

132 targeting PDE12, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-5688	99.96	73.23	4504

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 22.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• crystals of phosphodiesterase 12 belonged to space group P3(1)21 or P3(2)21, with unit-cell parameters a = b = 111.3, c = 192.4 A, and diffracted to 2.5 A resolution. (PMID:20445249)
• 2’-PDE locates to the mitochondrial matrix of human cells, and comprise an active 3’-5’ exoribonuclease exhibiting a preference for oligo-adenosine RNA like canonical cytoplasmic deadenylases. (PMID:21245038)
• 2’-phosphodiesterase is a mitochondrial protein that specifically removes poly(A) extensions from mitochondrial mRNAs both in vitro and in mitochondria of cultured cells. (PMID:21666256)
• PDE12 is a negative regulator of the antiviral innate immune response. (PMID:26055709)
• PDE12 in type 1 diabetes. (PMID:36307540)
• PDE12 disrupts mitochondrial oxidative phosphorylation and mediates mitochondrial dysfunction to induce oral mucosal epithelial barrier damage in oral submucous fibrosis. (PMID:38325798)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pde12	ENSDARG00000030964
mus_musculus	Pde12	ENSMUSG00000043702
rattus_norvegicus	Pde12	ENSRNOG00000059442
drosophila_melanogaster	CG31759	FBGN0051759
caenorhabditis_elegans		WBGENE00011268

Paralogs (5): ANGEL1 (ENSG00000013523), CNOT6 (ENSG00000113300), CNOT6L (ENSG00000138767), NOCT (ENSG00000151014), ANGEL2 (ENSG00000174606)

Protein

Protein identifiers

2’,5’-phosphodiesterase 12 — Q6L8Q7 (reviewed: Q6L8Q7)

Alternative names: Mitochondrial deadenylase

All UniProt accessions (2): Q6L8Q7, F6T1Q0

UniProt curated annotations — full annotation on UniProt →

Function. Enzyme that cleaves 2’,5’-phosphodiester bond linking adenosines of the 5’-triphosphorylated oligoadenylates, triphosphorylated oligoadenylates referred as 2-5A modulates the 2-5A system. Degrades triphosphorylated 2-5A to produce AMP and ATP. Also cleaves 3’,5’-phosphodiester bond of oligoadenylates. Plays a role as a negative regulator of the 2-5A system that is one of the major pathways for antiviral and antitumor functions induced by interferons (IFNs). Suppression of this enzyme increases cellular 2-5A levels and decreases viral replication in cultured small-airway epithelial cells and Hela cells.

Subcellular location. Mitochondrion matrix.

Tissue specificity. Ubiquitous.

Similarity. Belongs to the CCR4/nocturin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6L8Q7-1	1	yes
Q6L8Q7-2	2

RefSeq proteins (3): NP_001309105, NP_001309106, NP_808881* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005135	Endo/exonuclease/phosphatase	Domain
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily
IPR048821	PDE12-like_N	Domain
IPR050410	CCR4/nocturin_mRNA_transcr	Family

Pfam: PF03372, PF21171

UniProt features (61 total): strand 24, helix 19, binding site 3, turn 3, compositionally biased region 3, splice variant 2, region of interest 2, transit peptide 1, chain 1, modified residue 1, sequence variant 1, active site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
4Z0V	X-RAY DIFFRACTION	1.78
4Z2B	X-RAY DIFFRACTION	1.8
4ZKF	X-RAY DIFFRACTION	1.82

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6L8Q7-F1	90.45	0.82

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): 496 (proton donor/acceptor)

Ligand- & substrate-binding residues (3): 498; 351; 496

Post-translational modifications (1): 217

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8983711	OAS antiviral response

MSigDB gene sets: 224 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOMF_RNA_NUCLEASE_ACTIVITY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, GOMF_NUCLEASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_VIRAL_GENOME_REPLICATION, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_RESPONSE_TO_INTERFERON_ALPHA, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (11): nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:0000288), mitochondrial mRNA catabolic process (GO:0000958), mRNA processing (GO:0006397), cellular response to interferon-alpha (GO:0035457), regulation of mitochondrial mRNA stability (GO:0044528), positive regulation of viral genome replication (GO:0045070), defense response to virus (GO:0051607), cellular response to type II interferon (GO:0071346), cellular response to dsRNA (GO:0071359), nucleic acid metabolic process (GO:0090304), antiviral innate immune response (GO:0140374)

GO Molecular Function (7): 3’-5’-RNA exonuclease activity (GO:0000175), exonuclease activity (GO:0004527), poly(A)-specific ribonuclease activity (GO:0004535), metal ion binding (GO:0046872), catalytic activity (GO:0003824), nuclease activity (GO:0004518), hydrolase activity (GO:0016787)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	2
cellular response to cytokine stimulus	2
cytoplasm	2
nuclear-transcribed mRNA catabolic process	1
mRNA destabilization	1
mitochondrial RNA catabolic process	1
mRNA catabolic process	1
RNA processing	1
mRNA metabolic process	1
response to interferon-alpha	1
regulation of mRNA stability	1
viral genome replication	1
regulation of viral genome replication	1
positive regulation of viral process	1
defense response	1
response to virus	1
response to type II interferon	1
response to dsRNA	1
cellular response to nitrogen compound	1
nucleobase-containing compound metabolic process	1
macromolecule metabolic process	1
innate immune response	1
defense response to virus	1
3’-5’ exonuclease activity	1
RNA exonuclease activity, producing 5’-phosphomonoesters	1
nuclease activity	1
hydrolase activity, acting on ester bonds	1
3’-5’-RNA exonuclease activity	1
cation binding	1
molecular_function	1
catalytic activity, acting on a nucleic acid	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1278 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE12	RNASEL	Q05823	718
PDE12	SLIRP	Q9GZT3	697
PDE12	SUPV3L1	Q8IYB8	663
PDE12	LRPPRC	P42704	644
PDE12	MTPAP	Q9NVV4	617
PDE12	PARN	O95453	568
PDE12	AKAP7	O43687	560
PDE12	LACTB2	Q53H82	544
PDE12	TRNT1	Q96Q11	494
PDE12	CTBS	Q01459	482
PDE12	ELAC2	Q9BQ52	478
PDE12	PNPT1	Q8TCS8	475
PDE12	PNLDC1	Q8NA58	468
PDE12	RNGTT	O60942	466
PDE12	DEDD	O75618	464

IntAct

41 interactions, top by confidence:

A	B	Type	Score
PSMD10	PSMD11	psi-mi:“MI:0914”(association)	0.800
RTN4IP1	HEXIM1	psi-mi:“MI:0914”(association)	0.530
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
SIRT4	VWA8	psi-mi:“MI:0914”(association)	0.350
Rhoa	CLK2	psi-mi:“MI:0914”(association)	0.350
SGTB	ARHGAP32	psi-mi:“MI:0914”(association)	0.350
BAG6	CNOT1	psi-mi:“MI:0914”(association)	0.350
SORT1	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
INTS14	DKFZP586J0619	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
NCBP3	RSL1D1	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
CHCHD2	POLRMT	psi-mi:“MI:0914”(association)	0.350
CISD3	POLRMT	psi-mi:“MI:0914”(association)	0.350
NDUFA4	NDUFS8	psi-mi:“MI:0914”(association)	0.350
PTPMT1	TIMM44	psi-mi:“MI:0914”(association)	0.350
CHCHD2	ACSL4	psi-mi:“MI:0914”(association)	0.350
	SUPT5H	psi-mi:“MI:0914”(association)	0.350
UBL4A	BAG6	psi-mi:“MI:0914”(association)	0.350
JAZF1	TNPO2	psi-mi:“MI:0914”(association)	0.350
PDE12	LONP1	psi-mi:“MI:0914”(association)	0.350
PNPT1	PDE12	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
DNAJC30	UBA6	psi-mi:“MI:0914”(association)	0.350
LARS2	CREB1	psi-mi:“MI:0914”(association)	0.350
POMGNT2	FAM83G	psi-mi:“MI:0914”(association)	0.350

BioGRID (134): PDE12 (Co-fractionation), PDE12 (Co-fractionation), PDE12 (Affinity Capture-MS), PDE12 (Affinity Capture-MS), PDE12 (Affinity Capture-MS), PDE12 (Affinity Capture-MS), PDE12 (Affinity Capture-MS), PDE12 (Affinity Capture-MS), PDE12 (Affinity Capture-MS), PDE12 (Reconstituted Complex), PDE12 (Affinity Capture-MS), PDE12 (Biochemical Activity), PDE12 (Affinity Capture-MS), PDE12 (Affinity Capture-MS), PDE12 (Affinity Capture-MS)

ESM2 similar proteins: A0MTA1, A1YES6, A1YFZ3, A2T6Y4, A2T7I6, A5WVX1, B4FAT0, O54747, O94903, P0A2X3, P0A2X4, P13051, P23196, P26882, P27695, P28339, P28340, P28352, P36776, P43138, P52431, P97283, P97931, Q08752, Q08DF7, Q0J705, Q0V9S0, Q16775, Q32LH4, Q3B7M2, Q3T0G5, Q3TIU4, Q4P1V1, Q4R5U5, Q4R6C1, Q59HJ6, Q5R4Z1, Q5XIP6, Q5ZI23, Q653S9

Diamond homologs: A6H7I3, B2RYM0, C4V7I7, O35710, O74874, P79942, Q08DF7, Q24239, Q3TIU4, Q5RGT6, Q5VTE6, Q6AXQ5, Q6CEJ6, Q6L8Q7, Q8K1C0, Q8SU52, Q8VCU0, Q8VYU4, Q9ET55, Q9LS39, Q9UNK9, A2BHJ4, Q0WKY2, Q5BJ41, Q6AXU9, Q8K3P5, Q8VEG6, Q96LI5, Q9M2F8, Q9ULM6, A1CIJ6, A1CW67, A2Q9L0, A8MS41, B7XK66, P0CP22, P0CP23, P31384, Q0CT27, Q0U7W4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 58 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.

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to oxidative stress	5	15.2×	3e-03
mitochondrion organization	5	14.9×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2208 predictions. Top by Δscore:

Variant	Effect	Δscore
3:57559757:A:T	donor_gain	1.0000
3:57572294:TACCA:T	acceptor_gain	1.0000
3:57572295:ACCA:A	acceptor_gain	1.0000
3:57572296:CCA:C	acceptor_gain	1.0000
3:57572296:CCAC:C	acceptor_gain	1.0000
3:57572297:CA:C	acceptor_gain	1.0000
3:57572297:CAC:C	acceptor_gain	1.0000
3:57572298:ACTG:A	acceptor_loss	1.0000
3:57572299:C:CC	acceptor_gain	1.0000
3:57572301:G:C	acceptor_gain	1.0000
3:57575541:TACTT:T	donor_loss	1.0000
3:57575542:ACTTA:A	donor_loss	1.0000
3:57575543:CTTA:C	donor_gain	1.0000
3:57575544:TTAC:T	donor_loss	1.0000
3:57575545:TACTG:T	donor_loss	1.0000
3:57575546:A:AC	donor_gain	1.0000
3:57575546:AC:A	donor_loss	1.0000
3:57575547:C:CT	donor_gain	1.0000
3:57575547:CT:C	donor_gain	1.0000
3:57575547:CTG:C	donor_gain	1.0000
3:57575547:CTGT:C	donor_gain	1.0000
3:57575547:CTGTT:C	donor_gain	1.0000
3:57575669:AGAAG:A	acceptor_gain	1.0000
3:57575670:GAAG:G	acceptor_gain	1.0000
3:57575671:AAG:A	acceptor_gain	1.0000
3:57575672:AG:A	acceptor_gain	1.0000
3:57575674:C:CC	acceptor_gain	1.0000
3:57577312:TTAC:T	donor_loss	1.0000
3:57577313:TAC:T	donor_loss	1.0000
3:57577314:A:AC	donor_gain	1.0000

AlphaMissense

3963 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:57556803:T:A	W142R	1.000
3:57556803:T:C	W142R	1.000
3:57557370:C:A	R331S	1.000
3:57557431:A:T	E351V	1.000
3:57559840:T:C	F556L	1.000
3:57559842:T:A	F556L	1.000
3:57559842:T:G	F556L	1.000
3:57559946:C:A	P591H	1.000
3:57559964:C:T	S597F	1.000
3:57559967:A:T	D598V	1.000
3:57559969:C:G	H599D	1.000
3:57559970:A:C	H599P	1.000
3:57556572:C:A	R65S	0.999
3:57556805:G:C	W142C	0.999
3:57556805:G:T	W142C	0.999
3:57556822:T:C	L148P	0.999
3:57556938:T:C	F187L	0.999
3:57556940:T:A	F187L	0.999
3:57556940:T:G	F187L	0.999
3:57557266:G:C	R296P	0.999
3:57557280:A:G	N301D	0.999
3:57557282:C:A	N301K	0.999
3:57557282:C:G	N301K	0.999
3:57557341:G:A	C321Y	0.999
3:57557342:T:G	C321W	0.999
3:57557353:C:A	A325D	0.999
3:57557370:C:G	R331G	0.999
3:57557371:G:C	R331P	0.999
3:57557380:T:C	L334P	0.999
3:57557395:T:C	L339P	0.999

dbSNP variants (sampled 300 via entrez): RS1000012709 (3:57590290 G>A,C), RS1000042127 (3:57578636 C>T), RS1000101374 (3:57572123 G>A,T), RS1000132113 (3:57591927 G>T), RS1000153260 (3:57609311 T>C), RS1000155312 (3:57624819 G>A), RS1000178729 (3:57596438 C>T), RS1000238938 (3:57629400 C>T), RS1000284456 (3:57565420 T>C), RS1000303415 (3:57586800 G>A), RS1000357232 (3:57557667 C>T), RS1000358219 (3:57648723 G>A), RS1000389483 (3:57649056 G>A,T), RS1000418462 (3:57648381 C>G,T), RS1000457669 (3:57643138 T>C)

Disease associations

OMIM: gene MIM:616519 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
mitochondrial disease	Strong	Autosomal recessive

Mondo (1): mitochondrial disease (MONDO:0044970)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523342 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphodiesterases (other)

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 1 [PMID: 26055709]	Inhibition	9.1	pIC50
compound 3 [PMID: 26055709]	Inhibition	7.68	pIC50

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
9.10	IC50	0.8	nM	CHEMBL4556129
7.76	Ki	17.5	nM	CHEMBL5415518
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 10 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
3-[5-bromo-6-[(2S,3S)-2-(4-fluorophenyl)-3-(hydroxymethyl)morpholine-4-carbonyl]-1-methylbenzimidazol-2-yl]-1-ethylindole-6-carbonitrile	1625399: Inhibition of human PDE12 (17 to 609 residues) expresssed in Escherichia coli BL21(DE3) cells using 2-5A as substrate assessed as AMP monomers and ATP formation after 30 mins by AMP-Glo assay	ic50	0.0008	uM
3-[6-[3-(hydroxymethyl)-2-phenylmorpholine-4-carbonyl]-1-methylbenzimidazol-2-yl]-1H-indole-6-carbonitrile	1973677: Binding affinity to PDE12 (unknown origin) (17 to 609 residues) assessed as inhibition constant by AMP-glo reagent based assay	ki	0.0175	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178662: Inhibition of PDE12 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	6
bisphenol A	decreases expression, increases expression	2
deoxynivalenol	increases expression	2
Benzo(a)pyrene	increases expression, affects methylation	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	increases expression	1
2’,5’-oligoadenylate	affects binding, decreases activity, increases abundance	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
nivalenol	increases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Microplastics	increases expression, increases abundance	1
Antiviral Agents	affects binding, decreases activity, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Atrazine	decreases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4425341	Binding	Inhibition of human PDE12 (17 to 609 residues) expresssed in Escherichia coli BL21(DE3) cells using 2-5A as substrate assessed as AMP monomers and ATP formation after 30 mins by AMP-Glo assay	Chemical Space of DNA-Encoded Libraries. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT04378075	PHASE2/PHASE3	TERMINATED	A Study to Evaluate Efficacy and Safety of Vatiquinone for Treating Mitochondrial Disease in Participants With Refractory Epilepsy
NCT01642056	PHASE1/PHASE2	COMPLETED	EPI-743 for Metabolism or Mitochondrial Disorders
NCT03384420	PHASE1/PHASE2	COMPLETED	A Study to Evaluate the Safety and Therapeutic Effects of Transplantation of MNV-BM-BLD in Pediatric Patients With Pearson Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT01252979	EARLY_PHASE1	COMPLETED	Ketones & Mitochondrial Heteroplasmy
NCT00786539	Not specified	COMPLETED	Mitochondria Inborn Errors of Metabolism and ANT Defects in Mitochondria Diseases
NCT00829270	Not specified	COMPLETED	Economic and Medical Evaluation of the Whole Mitochondrial DNA Screening by Surveyor and Mitochips Techniques
NCT00831948	Not specified	UNKNOWN	Identification of Large-Scale Mutations of POLG Gene by QMPSF in Patients With Mitochondrial DNA Instability.
NCT01001585	Not specified	TERMINATED	Anesthetic Effects in Mitochondrial Disease
NCT01148550	Not specified	SUSPENDED	Longitudinal Study of Mitochondrial Hepatopathies