ACSS2

Summary

ACSS2 (acyl-CoA synthetase short chain family member 2, HGNC:15814) is a protein-coding gene on chromosome 20q11.22, encoding Acetyl-coenzyme A synthetase, cytoplasmic (Q9NR19). Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids.

This gene encodes a cytosolic enzyme that catalyzes the activation of acetate for use in lipid synthesis and energy generation. The protein acts as a monomer and produces acetyl-CoA from acetate in a reaction that requires ATP. Expression of this gene is regulated by sterol regulatory element-binding proteins, transcription factors that activate genes required for the synthesis of cholesterol and unsaturated fatty acids. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55902 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 123 total — 1 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_018677

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15814
Approved symbol	ACSS2
Name	acyl-CoA synthetase short chain family member 2
Location	20q11.22
Locus type	gene with protein product
Status	Approved
Aliases	ACS, ACSA, AceCS, dJ1161H23.1
Ensembl gene	ENSG00000131069
Ensembl biotype	protein_coding
OMIM	605832
Entrez	55902

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 34 protein_coding, 9 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay, 4 retained_intron

ENST00000253382, ENST00000360596, ENST00000461051, ENST00000464399, ENST00000467019, ENST00000468550, ENST00000470315, ENST00000473172, ENST00000475459, ENST00000476922, ENST00000477932, ENST00000480274, ENST00000480978, ENST00000481284, ENST00000481971, ENST00000484354, ENST00000488172, ENST00000490046, ENST00000490464, ENST00000491533, ENST00000493250, ENST00000493805, ENST00000494727, ENST00000497927, ENST00000871368, ENST00000871369, ENST00000871370, ENST00000871371, ENST00000871372, ENST00000871373, ENST00000871374, ENST00000871375, ENST00000871376, ENST00000871377, ENST00000871378, ENST00000871379, ENST00000871380, ENST00000918462, ENST00000918463, ENST00000918464, ENST00000957793, ENST00000957794, ENST00000957795, ENST00000957796, ENST00000957797, ENST00000957798, ENST00000957799, ENST00000957800, ENST00000957801, ENST00000957802, ENST00000957803, ENST00000957804

RefSeq mRNA: 3 — MANE Select: NM_018677 NM_001076552, NM_001242393, NM_018677

CCDS: CCDS13243, CCDS42868

Canonical transcript exons

ENST00000360596 — 18 exons

Exon	Start	End
ENSE00001893210	34876612	34876823
ENSE00003482804	34921330	34921462
ENSE00003499545	34921006	34921139
ENSE00003501527	34920539	34920709
ENSE00003508396	34913096	34913187
ENSE00003522612	34925698	34925766
ENSE00003531165	34919435	34919572
ENSE00003568105	34921544	34921600
ENSE00003580028	34923323	34923431
ENSE00003584160	34926877	34926951
ENSE00003591254	34913753	34913825
ENSE00003591834	34921786	34921866
ENSE00003630254	34914096	34914171
ENSE00003645627	34926105	34926281
ENSE00003662143	34882794	34882989
ENSE00003675474	34914323	34914437
ENSE00003786779	34913393	34913496
ENSE00003846039	34927087	34927959

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 99.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.1695 / max 1855.6799, expressed in 1806 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184266	15.7609	1666
184265	8.8896	1769
184264	1.6378	1099
184261	0.3500	99
184267	0.1838	62
184260	0.1648	79
184262	0.1060	65
184263	0.0767	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.31	gold quality
ileum	UBERON:0002116	99.21	silver quality
mucosa of transverse colon	UBERON:0004991	98.93	gold quality
rectum	UBERON:0001052	98.52	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.93	gold quality
transverse colon	UBERON:0001157	97.71	gold quality
mucosa of stomach	UBERON:0001199	97.65	gold quality
tibialis anterior	UBERON:0001385	97.65	gold quality
right adrenal gland cortex	UBERON:0035827	97.51	gold quality
right lung	UBERON:0002167	97.49	gold quality
gastrocnemius	UBERON:0001388	97.42	gold quality
apex of heart	UBERON:0002098	97.40	gold quality
upper arm skin	UBERON:0004263	97.40	gold quality
kidney epithelium	UBERON:0004819	97.35	gold quality
right adrenal gland	UBERON:0001233	97.27	gold quality
pancreatic ductal cell	CL:0002079	97.19	gold quality
colonic epithelium	UBERON:0000397	97.15	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.14	gold quality
muscle of leg	UBERON:0001383	97.09	gold quality
upper lobe of left lung	UBERON:0008952	96.95	gold quality
left adrenal gland	UBERON:0001234	96.93	gold quality
left adrenal gland cortex	UBERON:0035825	96.93	gold quality
lower esophagus mucosa	UBERON:0035834	96.89	gold quality
body of stomach	UBERON:0001161	96.78	gold quality
upper lobe of lung	UBERON:0008948	96.76	gold quality
small intestine	UBERON:0002108	96.72	gold quality
adrenal cortex	UBERON:0001235	96.70	gold quality
subcutaneous adipose tissue	UBERON:0002190	96.60	gold quality
heart left ventricle	UBERON:0002084	96.59	gold quality
right lobe of liver	UBERON:0001114	96.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, SP3, SREBF1, SREBF2

miRNA regulators (miRDB)

37 targeting ACSS2, 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-1468-3P	99.96	72.74	3797
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-155-3P	99.03	67.99	924
HSA-MIR-452-3P	99.01	66.25	1241
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-12126	98.09	64.82	637
HSA-MIR-1245B-3P	98.01	68.91	1387

Literature-anchored findings (GeneRIF, showing 29)

• Because the activity of a bacterial ortholog of AceCS2, called ACS, is controlled via deacetylation by a bacterial sirtuin protein, our observation highlights the conservation of a metabolic regulatory pathway from bacteria to humans (PMID:16788062)
• The patterns of (18)F-FDG and (11)C-acetate uptake seemed to complement each other in both human HCC and HCC cell lines. (PMID:19617323)
• Ritonavir (at 100 mg once daily and 100 mg twice daily significantly down-regulated acyl-CoA synthetase short-chain family member 2 in 20 healthy individuals. (PMID:20353815)
• During hypoxia, ACSS2 modulates interactions of the acetylase/coactivator CBP with the stress-responsive transcription factor, HIF-2. These interactions include acetylation of HIF-2 by CBP as well as stable HIF-2/CBP complex formation, both of which are required for maximal HIF-2 signaling. Thus, ACSS2 links changes in metabolism that occur during stress with activation of a selective nuclear signaling pathway. (PMID:25108527)
• Observations suggest that ACSS2 is expressed to a significant extent in particular tumor types, including triple-negative breast cancers. (PMID:25525877)
• Study shows that ACSS2 is upregulated in the human orthotopic tumor and primary human tumors, as well as a murine glioma model; the tumors do not oxidize [U-(13)C]glutamine. In vivo oxidation of [1,2-(13)C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. (PMID:25525878)
• Study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. (PMID:25584894)
• Loss of ACSS2 expression is associated with with gastric cancer. (PMID:26381042)
• ACSS2 is essential for glucose-independent acetate-mediated cell survival and tumor growth. (PMID:27539851)
• these findings suggest that downregulation of acetyl-CoA synthetase-2 expression is a metabolic hallmark of tumor progression and aggressive behavior in colorectal carcinoma. (PMID:27713423)
• The nuclear-cytosolic acetyl-CoA synthetase 2 recaptures acetate released from histone deacetylation for recycling by histone acetyltransferases. (PMID:28099844)
• ACLY and ACSS2 are both activated to produce cytosolic Ac-CoA from glucose carbon for lipogenesis during human cytomegalovirus infection. (PMID:28167750)
• In a Honduran population, the odds of having nonsyndromic cleft lip/palate (NSCLP) among carriers of the ACSS2 variant was 4.0 with a carrier frequency of 7.1% in unrelated affected and 1.9% in unrelated unaffected individuals. In a Colombian population, the odds of having NSCLP among carriers of the ACSS2 variant was 2.6 with a carrier frequency of 10.0% in unrelated affected and 4.1% in unrelated unaffected individuals. (PMID:28543373)
• Results suggest that ACSS2 gene is associated with human alcoholism and ethanol intake in a free-choice animal model, and even the compulsive-like behavior associated with ethanol use. Finally, slight alterations in metabolism could be responsible for the difference between ethanol non-preferring, ethanol-preferring and compulsive-like ethanol consumption. (PMID:28550509)
• In the nucleus, ACSS2 binds to transcription factor EB and translocates to lysosomal and autophagy gene promoter regions, where ACSS2 incorporates acetate generated from histone acetylation turnover to locally produce acetyl-CoA for histone H3 acetylation in these regions and promote lysosomal biogenesis, autophagy, cell survival, and brain tumorigenesis. (PMID:28552616)
• A novel biologic role for ACSS2 in recycling of nuclear acetate for histone acetylation to promote lysosomal and autophagy-related gene expression and counteract nutritional stress, highlighting the importance of ACSS2 in maintaining autophagy and lysosome-mediated cellular energy homeostasis during tumor development. (PMID:28820290)
• Exogenous acetate augments Acss2/HIF-2 dependent cancer growth and metastasis in cell culture and mouse models (PMID:29281714)
• ACSS2 is an important factor for promoting RCC development and is essential for cell migration and invasion, which it promotes by increasing the expression of LAMP1. (PMID:29444517)
• ACSS2-driven histone crotonylation reverses HIV latency (PMID:29457784)
• High ACSS2 expression is associated with renal cell carcinoma. (PMID:29503142)
• the alternative transcription start site selection of ACSS2 was significantly different between hepatocellular carcinoma and corresponding adjacent tissues. (PMID:31076106)
• Low ACSS2 expression is associated with Abdominal Aortic Aneurysm. (PMID:31730405)
• Silencing ACSS2 expression inhibits migration and invasion of cervical cancer cells induced by nutrient stress, which is related to down-regulated Wnt/beta-catenin signaling pathway activity. (PMID:31814569)
• Mammalian acetate-dependent acetyl CoA synthetase 2 contains multiple protein destabilization and masking elements. (PMID:34343565)
• O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation. (PMID:35190642)
• Acetyl-Coenzyme A Synthetase 2 Potentiates Macropinocytosis and Muscle Wasting Through Metabolic Reprogramming in Pancreatic Cancer. (PMID:35777482)
• ACSS2-mediated NF-kappaB activation promotes alkaliptosis in human pancreatic cancer cells. (PMID:36707625)
• ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules. (PMID:38051585)
• Proteomic profiling reveals ACSS2 facilitating metabolic support in acute myeloid leukemia. (PMID:38851813)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	acss2	ENSDARG00000037781
mus_musculus	Acss2	ENSMUSG00000027605
rattus_norvegicus	Acss2	ENSRNOG00000018755
drosophila_melanogaster	AcCoAS	FBGN0012034
caenorhabditis_elegans		WBGENE00007969

Paralogs (13): ACSM3 (ENSG00000005187), ACSM2B (ENSG00000066813), AACS (ENSG00000081760), ACSS3 (ENSG00000111058), ACSS1 (ENSG00000154930), AASDH (ENSG00000157426), ACSM1 (ENSG00000166743), ACSF2 (ENSG00000167107), ACSM6 (ENSG00000173124), ACSF3 (ENSG00000176715), ACSM5 (ENSG00000183549), ACSM2A (ENSG00000183747), ACSM4 (ENSG00000215009)

Protein

Protein identifiers

Acetyl-coenzyme A synthetase, cytoplasmic — Q9NR19 (reviewed: Q9NR19)

Alternative names: Acetate–CoA ligase, Acetyl-CoA synthetase, Acetyl-CoA synthetase 1, Acyl-CoA synthetase short-chain family member 2, Acyl-activating enzyme, Propionate–CoA ligase

All UniProt accessions (10): Q9NR19, B4DEH9, C9IYL0, C9J7L5, C9JXD9, C9JY31, F8WBQ7, F8WC73, F8WCJ4, F8WDJ9

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the synthesis of acetyl-CoA from short-chain fatty acids. Acetate is the preferred substrate. Can also utilize propionate with a much lower affinity. Nuclear ACSS2 promotes glucose deprivation-induced lysosomal biogenesis and autophagy, tumor cell survival and brain tumorigenesis. Glucose deprivation results in AMPK-mediated phosphorylation of ACSS2 leading to its translocation to the nucleus where it binds to TFEB and locally produces acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes thereby activating their transcription. The regulation of genes associated with autophagy and lysosomal activity through ACSS2 is important for brain tumorigenesis and tumor survival. Acts as a chromatin-bound transcriptional coactivator that up-regulates histone acetylation and expression of neuronal genes. Can be recruited to the loci of memory-related neuronal genes to maintain a local acetyl-CoA pool, providing the substrate for histone acetylation and promoting the expression of specific genes, which is essential for maintaining long-term spatial memory.

Subunit / interactions. Monomer. Interacts with TFEB. AMPK-mediated phosphorylated form at Ser-659 interacts with KPNA1; this interaction results in nuclear translocation of ACSS2. Interacts with the ‘Thr-172’ phosphorylated form of PRKAA2. Interacts with CREBBP.

Subcellular location. Cytoplasm. Cytosol. Nucleus.

Post-translational modifications. Reversibly acetylated at Lys-661. The acetyl-CoA synthase activity is inhibited by acetylation and activated by deacetylation mediated by the deacetylases SIRT1 and SIRT3. Glucose deprivation results in its AMPK-dependent phosphorylation at Ser-659, which leads to exposure of its nuclear localization signal, required for its interaction with KPNA1 and subsequent translocation to the nucleus.

Activity regulation. Inhibited by acetylation at Lys-661 and activated by deacetylation mediated by the deacetylases SIRT1 and SIRT3.

Similarity. Belongs to the ATP-dependent AMP-binding enzyme family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NR19-1	1	yes
Q9NR19-2	2

RefSeq proteins (3): NP_001070020, NP_001229322, NP_061147* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000873	AMP-dep_synth/lig_dom	Domain
IPR011904	Ac_CoA_lig	Family
IPR020845	AMP-binding_CS	Conserved_site
IPR025110	AMP-bd_C	Domain
IPR032387	ACAS_N	Domain
IPR042099	ANL_N_sf	Homologous_superfamily
IPR045851	AMP-b_sf	Homologous_superfamily

Pfam: PF00501, PF13193, PF16177

Enzyme classification (BRENDA):

• EC 6.2.1.1 — acetate-CoA ligase (BRENDA: 56 organisms, 173 substrates, 59 inhibitors, 236 Km, 149 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ACETATE	0.035–11000	53
ATP	0.017–17	41
COA	0.011–1.2	36
PROPIONATE	0.62–188.8	16
BUTYRATE	0.19–151.9	12
VALERATE	0.4–11.1	7
4-METHYLVALERATE	0.07–7.6	6
ACETYL-COA	0.0037–1.8	6
HEPTANOATE	0.71–10.2	6
HEXANOATE	0.13–12.6	6
OCTANOATE	2.1–48	6
3-METHYLVALERATE	0.04–125	5
ISOBUTYRATE	0.15–219	5
PROPANOATE	3.1–10.5	5
SODIUM ACETATE	0.25–4.66	5

Catalyzed reactions (Rhea), 2 shown:

• propanoate + ATP + CoA = propanoyl-CoA + AMP + diphosphate (RHEA:20373)
• acetate + ATP + CoA = acetyl-CoA + AMP + diphosphate (RHEA:23176)

UniProt features (28 total): modified residue 9, binding site 8, mutagenesis site 3, sequence conflict 3, region of interest 2, chain 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR19-F1	90.14	0.74

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 (8): 575; 636; 219–222; 363; 439–441; 463–468; 552; 567

Post-translational modifications (9): 28, 30, 36, 263, 265, 267, 418, 659, 661

Mutagenesis-validated functional residues (3):

Position	Phenotype
363	loss of catalytic activity but no effect on its nuclear translocation upon glucose deprivation. loss of ability to promo
659	no effect on catalytic activity. loss of ampk-mediated phosphorylation, interaction with kpna1 and nuclear translocation
664–665	no effect on catalytic activity. loss of interaction with kpna1 and nuclear translocation upon glucose deprivation. loss

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-71384	Ethanol oxidation
R-HSA-1430728	Metabolism
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-211859	Biological oxidations
R-HSA-211945	Phase I - Functionalization of compounds

MSigDB gene sets: 204 (showing top): GOBP_MEMORY, REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_COGNITION, GOBP_BEHAVIOR, NIKOLSKY_BREAST_CANCER_20Q11_AMPLICON, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ACETYL_COA_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS

GO Biological Process (9): ethanol catabolic process (GO:0006068), acetyl-CoA biosynthetic process (GO:0006085), long-term memory (GO:0007616), lipid biosynthetic process (GO:0008610), acetate biosynthetic process (GO:0019413), obsolete acetyl-CoA biosynthetic process from acetate (GO:0019427), propionate biosynthetic process (GO:0019542), lipid metabolic process (GO:0006629), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (9): chromatin binding (GO:0003682), transcription coactivator activity (GO:0003713), acetyl-CoA synthetase activity (GO:0003987), ATP binding (GO:0005524), AMP binding (GO:0016208), propionate-CoA ligase activity (GO:0050218), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (4): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrial matrix (GO:0005759), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Mitochondrial biogenesis	1
Phase I - Functionalization of compounds	1
Organelle biogenesis and maintenance	1
Metabolism	1
Biological oxidations	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
adenyl ribonucleotide binding	2
cellular anatomical structure	2
ethanol metabolic process	1
primary alcohol catabolic process	1
acetyl-CoA metabolic process	1
acyl-CoA biosynthetic process	1
memory	1
lipid metabolic process	1
biosynthetic process	1
acetate metabolic process	1
monocarboxylic acid biosynthetic process	1
propionate metabolic process	1
short-chain fatty acid biosynthetic process	1
primary metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
CoA-ligase activity	1
purine ribonucleoside triphosphate binding	1
anion binding	1
cation binding	1
short-chain fatty acid-CoA ligase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
mitochondrion	1
intracellular organelle lumen	1
cytoplasm	1

Protein interactions and networks

STRING

2532 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACSS2	ACLY	P53396	849
ACSS2	FASN	P49327	721
ACSS2	ACACA	Q13085	670
ACSS2	ACSL1	P33121	633
ACSS2	PPARGC1A	Q9UBK2	627
ACSS2	GPAM	Q9HCL2	623
ACSS2	ACOT12	Q8WYK0	608
ACSS2	PHGDH	O43175	604
ACSS2	EP300	Q09472	590
ACSS2	SREBF1	P36956	586
ACSS2	PC	P11498	573
ACSS2	TFEB	P19484	573
ACSS2	CS	O75390	572
ACSS2	ACACB	O00763	568
ACSS2	IDH2	P48735	566
ACSS2	HMGCS1	Q01581	566

IntAct

9 interactions, top by confidence:

A	B	Type	Score
C	ACSS2	psi-mi:“MI:0915”(physical association)	0.370
CTR9	POLR2B	psi-mi:“MI:0914”(association)	0.350
Smchd1	SETD1A	psi-mi:“MI:0914”(association)	0.350
PRPS2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
PRPS2	ARHGEF37	psi-mi:“MI:0914”(association)	0.350
	MYO1C	psi-mi:“MI:0914”(association)	0.350
purT	ACSS2	psi-mi:“MI:0915”(physical association)	0.000
UPF1	ACSS2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): ACSS2 (Co-fractionation), CAD (Co-fractionation), WARS (Co-fractionation), ACSS2 (Affinity Capture-MS), ACSS2 (Affinity Capture-MS), ACSS2 (Affinity Capture-MS), ACSS2 (Affinity Capture-RNA), ACSS2 (Affinity Capture-MS), ACSS2 (Affinity Capture-MS), ACSS2 (Co-fractionation), ACSS2 (Co-fractionation), ACSS2 (Affinity Capture-MS), ACSS2 (Affinity Capture-MS), ACSS2 (Cross-Linking-MS (XL-MS)), ACSS2 (Proximity Label-MS)

ESM2 similar proteins: A0A0G2K047, A0KNI2, A1U2S9, A4G3L8, A4SJM6, A6UED8, A6WXV8, A7MB45, A8PDE3, B2JD61, B3PS41, B9DGD6, B9JEV4, B9JV43, C3MAS0, O13440, O60011, O68040, O94049, P16928, P16929, P31638, P36333, P52910, P78773, Q01574, Q01576, Q14DH7, Q27549, Q2K2T1, Q54Z60, Q554Z5, Q5REB8, Q6BQF2, Q6BS00, Q6FLU2, Q6FXI2, Q6MNF1, Q750T7, Q758X0

Diamond homologs: A0A0A2J5U8, A1U2S9, B2KWI3, C1AA44, J5JLF2, K0E2F3, O07610, O53521, O68040, P13129, P16929, P27095, P38135, P63521, P63522, P69451, P69452, P94547, P9WQ44, P9WQ45, Q07VK4, Q0AFF1, Q0K844, Q0P4F7, Q15YI8, Q17QJ1, Q26304, Q336M7, Q42524, Q42982, Q499N5, Q4R3Y4, Q4WR83, Q54P78, Q5RDY4, Q5SIW6, Q6BS00, Q6MNF1, Q6P1M0, Q72J95

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
PRKAA1	“up-regulates activity”	ACSS2	phosphorylation
AMPK	“up-regulates activity”	ACSS2	phosphorylation
ACSS2	“up-regulates quantity”	acetyl-CoA(4-)	“chemical modification”
ACSS2	“down-regulates quantity”	acetate	“chemical modification”
ACSS2	“down-regulates quantity”	“coenzyme A(4-)”	“chemical modification”
ACSS2	“up-regulates quantity by expression”	CTSA	“transcriptional regulation”
ACSS2	“up-regulates quantity by expression”	GBA	“transcriptional regulation”
ACSS2	“up-regulates quantity by expression”	GUSB	“transcriptional regulation”
ACSS2	“up-regulates quantity by expression”	LAMP1	“transcriptional regulation”
ACSS2	“up-regulates quantity by expression”	PPM1D	“transcriptional regulation”
ACSS2	“up-regulates quantity by expression”	BECN1	“transcriptional regulation”
ACSS2	“up-regulates quantity by expression”	MAP1LC3B	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	78
Likely benign	15
Benign	7

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
153447	GRCh38/hg38 20q11.21-11.23(chr20:32062768-35906606)x3	Pathogenic
1808687	GRCh37/hg19 20q11.21-11.23(chr20:29833535-34815537)x3	Likely pathogenic

SpliceAI

3045 predictions. Top by Δscore:

Variant	Effect	Δscore
20:34872610:C:A	donor_gain	1.0000
20:34882971:A:G	donor_gain	1.0000
20:34913186:GG:G	donor_gain	1.0000
20:34913187:GG:G	donor_gain	1.0000
20:34913392:GGC:G	acceptor_gain	1.0000
20:34913493:TGTG:T	donor_loss	1.0000
20:34913497:GTAG:G	donor_loss	1.0000
20:34913498:T:A	donor_loss	1.0000
20:34914169:GAA:G	donor_gain	1.0000
20:34914172:G:GG	donor_gain	1.0000
20:34914321:AG:A	acceptor_gain	1.0000
20:34914322:GG:G	acceptor_gain	1.0000
20:34919544:ACACC:A	donor_gain	1.0000
20:34919563:C:T	donor_gain	1.0000
20:34920537:AG:A	acceptor_gain	1.0000
20:34920538:GG:G	acceptor_gain	1.0000
20:34920538:GGGT:G	acceptor_gain	1.0000
20:34921459:GACA:G	donor_gain	1.0000
20:34921463:G:GG	donor_gain	1.0000
20:34923317:CCCCA:C	acceptor_loss	1.0000
20:34923319:CCAG:C	acceptor_loss	1.0000
20:34923320:CAGGT:C	acceptor_loss	1.0000
20:34923322:GGT:G	acceptor_gain	1.0000
20:34923400:G:GT	donor_gain	1.0000
20:34923428:GATG:G	donor_gain	1.0000
20:34923430:TGGTG:T	donor_loss	1.0000
20:34923431:GGTGA:G	donor_loss	1.0000
20:34923432:G:GA	donor_loss	1.0000
20:34923432:G:GG	donor_gain	1.0000
20:34923433:T:G	donor_loss	1.0000

AlphaMissense

4601 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:34913753:T:C	F191L	1.000
20:34913755:T:A	F191L	1.000
20:34913755:T:G	F191L	1.000
20:34920647:T:A	W361R	1.000
20:34920647:T:C	W361R	1.000
20:34913762:T:C	F194L	0.999
20:34913764:C:A	F194L	0.999
20:34913764:C:G	F194L	0.999
20:34919549:A:C	S317R	0.999
20:34919551:T:A	S317R	0.999
20:34919551:T:G	S317R	0.999
20:34919553:G:A	G318D	0.999
20:34920645:G:A	G360D	0.999
20:34920649:G:C	W361C	0.999
20:34920649:G:T	W361C	0.999
20:34882921:C:A	N102K	0.998
20:34882921:C:G	N102K	0.998
20:34913787:G:C	R202P	0.998
20:34920631:C:G	C355W	0.998
20:34920639:A:T	D358V	0.998
20:34920657:G:A	G364D	0.998
20:34920705:T:A	V380D	0.998
20:34921045:T:A	W395R	0.998
20:34921045:T:C	W395R	0.998
20:34921448:T:A	W466R	0.998
20:34921448:T:C	W466R	0.998
20:34913143:T:C	L141P	0.997
20:34913471:G:C	R182P	0.997
20:34913753:T:A	F191I	0.997
20:34919550:G:T	S317I	0.997

dbSNP variants (sampled 300 via entrez): RS1000069485 (20:34909720 T>C), RS1000092710 (20:34902377 G>A), RS1000147213 (20:34895960 C>T), RS1000196567 (20:34873296 C>T), RS1000212328 (20:34876941 G>A), RS1000351182 (20:34888530 T>G), RS1000612432 (20:34899867 C>T), RS1000631300 (20:34902810 C>G,T), RS1000659615 (20:34882033 T>A,C), RS1000716307 (20:34875251 G>A), RS1000786225 (20:34914881 C>T), RS1000817899 (20:34922642 C>T), RS1000821306 (20:34888863 G>C), RS1000872134 (20:34880295 G>A), RS1000911141 (20:34893939 C>G)

Disease associations

OMIM: gene MIM:605832 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST005956_31	Waist-to-hip ratio adjusted for BMI	8.000000e-08
GCST005958_16	Waist-to-hip ratio adjusted for BMI (age >50)	6.000000e-06
GCST005962_40	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-08
GCST006941_38	Irritable mood	1.000000e-10
GCST007876_125	Estimated glomerular filtration rate	7.000000e-18
GCST008103_149	Bipolar disorder	3.000000e-06
GCST010142_10	Fish- and plant-related diet	8.000000e-12
GCST012227_1087	Hip circumference adjusted for BMI	4.000000e-10
GCST90020028_1516	Hip circumference adjusted for BMI	1.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009594	irritability measurement
EFO:0008111	diet measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523467 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs17309872	Efficacy	3	carboplatin;cisplatin;docetaxel;gemcitabine;paclitaxel	Non-Small Cell Lung Carcinoma
rs6088638	Toxicity	3	ethanol	Alcohol abuse

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs17309872	ACSS2, GSS	3	3.00	1	carboplatin;cisplatin;docetaxel;gemcitabine;paclitaxel
rs6088638	ACSS2	3	1.75	1	ethanol
rs7266550	ACSS2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Acyl-CoA synthetases

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

Ligand	Action	Affinity	Parameter
example 265 [WO2019097515A1]	Inhibition	8.35	pIC50

Binding affinities (BindingDB)

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

Ligand	Measure	Value	Patent
N-(3-(cyclobutyldifluoromethyl)phenyl)-1-(4-(difluoromethoxy)phenyl)-3-methyl-5-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
US12441689, Compound 109	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
US12441689, Compound 110	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
2-(4-(difluoromethoxy)phenyl)-N-(3-(1,1-difluoropropyl)phenyl)-5-methyloxazole-4-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
1-(5-benzyl-6-methoxy-[1,1’-biphenyl]-3-yl)-N-(3-(1,1-difluoropropyl)phenyl)-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
1-(5-(cyclohexylmethyl)-6-methoxy-[1,1biphenyl]-3-yl)-N-(3-(1,1-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-2-(6-(difluoromethoxy)-[1,1’-biphenyl]-3-yl)-6-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-[3-(1,1-difluoroethyl)phenyl]-5-[4-(difluoromethoxy)-3-phenyl-phenyl]-3-methyl-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoropropyl)phenyl)-2-(4-methoxyphenyl)-4-methyloxazole-5-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
2-(4-(difluoromethoxy)phenyl)-N-(3-(1,1-difluoropropyl)phenyl)-6-methylpyrimidine-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
5-cyclopropyl-N-[3-(1,1-difluoroethyl)phenyl]-1-[4- (difluoromethoxy)phenyl]-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-2-(4-(difluoromethoxy)phenyl)-6-methylpyrimidine-4-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-1-(4-(difluoromethoxy)phenyl)-4-ethyl-3-methyl-5-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-1-(4-(difluoromethoxy)phenyl)-3-methyl-5-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-1-(4-(difluoromethoxy)phenyl)-5-(dimethylamino)-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
4-chloro-N-(3-(1,1-difluoroethyl)phenyl)-1-(4-(difluoromethoxy)phenyl)-3-methyl-5-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-[3-(1,1-difluoroethyl)phenyl]-1-[4-(difluoromethoxy)-3-(2-pyridyl)phenyl]-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-1-(2’-(difluoromethoxy)-[1,1’:3’,1’-terphenyl]-5’-yl)-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-1-(4-(difluoromethoxy)-3-(pyridin-2-yl)phenyl)-3,5-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-1-(4-(difluoromethoxy)-3-(pyridin-3-yl)phenyl)-3,5-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-[3-(1,1-difluoroethyl)phenyl]-1-(4-methoxy-3-methyl-5-phenyl-phenyl)-3-methyl-5-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-1-(4-(difluoromethoxy)-3-(pyridin-4-yl)phenyl)-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-1-(4-(difluoromethoxy)-3-(pyridin-3-yl)phenyl)-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-1-(6-(difluoromethoxy)-[1,1’-biphenyl]-3-yl)-3-methyl-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
4-((3-(1,1-difluoroethyl)phenyl)carbamoyl)-1-(4-methoxyphenyl)-3-methyl-1H-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
4-((3-(1,1-difluoroethyl)phenyl)carbamoyl)-1-(4-(difluoromethoxy)phenyl)-3-methyl-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
4-((3-(1,1-difluoroethyl)phenyl)carbamoyl)-1-(4-(difluoromethoxy)-3-(pyridin-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-[3-(1,1-difluoroethyl)phenyl]-1-[4-(difluoromethoxy) phenyl]-5-(hydroxymethyl)-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-[3-(1,1-difluoroethyl)phenyl]-1-[4-(difluoromethoxy)phenyl]-3-methylpyrazole-4-carboxamide	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-[3-(1,1-difluoroethyl)phenyl]-1-[4-(difluoromethoxy)phenyl]-5-methoxy-3-methylpyrazole-4-carboxamide	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
4-chloro-N-[3-(1,1-difluoroethyl)phenyl]-1-(4-methoxyphenyl)-3-methyl-5-oxopyrazole-4-carboxamide	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
1-(5-(4-chlorobenzyl)-6-methoxy-[1,1’-biphenyl]-3-yl)-N-(3-(1,1-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoropropyl)phenyl)-1-(6-methoxy-5-propyl-[1,1’-biphenyl]-3-yl)-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-1-(5-(4-hydroxybenzyl)-6-methoxy- [1,1’-biphenyl]-3-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoropropyl)phenyl)-5-fluoro-1-(4-methoxyphenyl)-3-methyl-1H-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
1-(5-(4-chlorobenzyl)-6-methoxy-[1,1’-biphenyl]-3-yl)-N-(3-(1,1-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
N-(3-(1,1-difluoroethyl)phenyl)-2-(4-methoxyphenyl)-5-methylpyrimidine-4-	IC50	55 nM	US-12441689: ACSS2 inhibitors and methods of use thereof
US20250213546, Compound AD-4859	KD	52000 nM	US-20250213546: TREATING CANCER WITH SMALL MOLECULES THAT INHIBIT ACSS-2
4-hydroxy-1-methyl-N-[2-(2-phenoxyphenyl)ethyl]piperidine-4-carboxamide	KD	53000 nM	US-20250213546: TREATING CANCER WITH SMALL MOLECULES THAT INHIBIT ACSS-2
N-[3-(furan-2-yl)-3-phenylpropyl]-2-(8-methylimidazo[1,2-a]pyridin-3-yl)acetamide	KD	67000 nM	US-20250213546: TREATING CANCER WITH SMALL MOLECULES THAT INHIBIT ACSS-2
(1-aminocyclopropyl)-(3,3-diphenylpiperidin-1-yl)methanone	KD	80000 nM	US-20250213546: TREATING CANCER WITH SMALL MOLECULES THAT INHIBIT ACSS-2
(2S)-2-amino-1-(3,3-diphenylpiperidin-1-yl)propan-1-one	KD	85000 nM	US-20250213546: TREATING CANCER WITH SMALL MOLECULES THAT INHIBIT ACSS-2
(2S)-2-amino-2-cyclopropyl-1-(3,3-diphenylpiperidin-1-yl)ethanone	KD	89000 nM	US-20250213546: TREATING CANCER WITH SMALL MOLECULES THAT INHIBIT ACSS-2
N-cyclopropyl-3-(3,3-diphenylpiperidin-1-yl)propanamide	KD	105000 nM	US-20250213546: TREATING CANCER WITH SMALL MOLECULES THAT INHIBIT ACSS-2
N-(3,3-diphenylpropyl)-2-pyrrolidin-3-ylacetamide	KD	116000 nM	US-20250213546: TREATING CANCER WITH SMALL MOLECULES THAT INHIBIT ACSS-2
US20250213546, Compound AD-5584	KD	161000 nM	US-20250213546: TREATING CANCER WITH SMALL MOLECULES THAT INHIBIT ACSS-2

ChEMBL bioactivities

272 potent at pChembl≥5 of 272 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	IC50	0.01	nM	CHEMBL4846168
11.00	IC50	0.01	nM	CHEMBL4873965
11.00	IC50	0.01	nM	CHEMBL4850648
11.00	IC50	0.01	nM	CHEMBL4876400
11.00	IC50	0.01	nM	CHEMBL4867121
11.00	IC50	0.01	nM	CHEMBL4848186
11.00	IC50	0.01	nM	CHEMBL4870590
11.00	IC50	0.01	nM	CHEMBL4853889
11.00	IC50	0.01	nM	CHEMBL4855352
11.00	IC50	0.01	nM	CHEMBL4859117
11.00	IC50	0.01	nM	CHEMBL4862805
9.48	IC50	0.33	nM	CHEMBL4550594
9.34	IC50	0.4626	nM	CHEMBL4449652
9.00	IC50	1	nM	CHEMBL4535842
9.00	IC50	1	nM	CHEMBL4867121
9.00	IC50	1	nM	CHEMBL4848186
9.00	IC50	1	nM	CHEMBL4873965
9.00	IC50	1	nM	CHEMBL4876400
9.00	IC50	1	nM	CHEMBL4850648
9.00	IC50	1	nM	CHEMBL4855352
9.00	IC50	1	nM	CHEMBL4859117
9.00	IC50	1	nM	CHEMBL4870878
9.00	IC50	1	nM	CHEMBL4862805
9.00	IC50	1	nM	CHEMBL4870590
8.96	IC50	1.1	nM	CHEMBL4473187
8.68	IC50	2.1	nM	CHEMBL4463979
8.57	IC50	2.66	nM	CHEMBL4560160
8.49	IC50	3.2	nM	CHEMBL4548954
8.41	IC50	3.9	nM	CHEMBL4476365
8.40	IC50	4	nM	CHEMBL4466204
8.35	IC50	4.5	nM	CHEMBL4539904
8.30	IC50	5	nM	CHEMBL4437243
7.30	IC50	50	nM	CHEMBL4520185
7.30	IC50	50	nM	CHEMBL4570201
7.30	IC50	50	nM	CHEMBL4515458
7.30	IC50	50	nM	CHEMBL4546463
7.30	IC50	50	nM	CHEMBL4572762
7.30	IC50	50	nM	CHEMBL4582559
7.30	IC50	50	nM	CHEMBL4570193
7.30	IC50	50	nM	CHEMBL4513710
7.30	IC50	50	nM	CHEMBL4546851
7.30	IC50	50	nM	CHEMBL4531943
7.30	IC50	50	nM	CHEMBL4557579
7.30	IC50	50	nM	CHEMBL4555596
7.30	IC50	50	nM	CHEMBL4529333
7.30	IC50	50	nM	CHEMBL4559252
7.30	IC50	50	nM	CHEMBL4531805
7.30	IC50	50	nM	CHEMBL4536668
7.30	IC50	50	nM	CHEMBL4539409
7.30	IC50	50	nM	CHEMBL4534808

PubChem BioAssay actives

48 with measured affinity, of 48 total; 24 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-[3-(1,1-difluoroethyl)phenyl]-1-[4-(difluoromethoxy)-3-pyridin-4-ylphenyl]-3-methyl-5-oxo-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	<0.0001	uM
2-[[4-(difluoromethoxy)phenyl]-(2-fluorophenyl)-hydroxymethyl]-1-ethyl-N-(1-ethyl-1,2,4-triazol-3-yl)-5-methoxyimidazo[4,5-b]pyridine-6-carboxamide	1772177: Inhibition of human recombinant ACSS2 incubated for 180 mins by AMP Glo assay	ic50	<0.0001	uM
[1-ethyl-5-methoxy-6-(2H-tetrazol-5-yl)imidazo[4,5-b]pyridin-2-yl]-phenyl-(1,3-thiazol-2-yl)methanol	1782628: Inhibition of ACSS2 in human HCT-15 cells assessed as inhibition of 14C acetate incorporation into fatty acids measured after 24 hrs by scintillation counting based cellular lipids assay	ic50	<0.0001	uM
[1-ethyl-5-methoxy-6-(2H-tetrazol-5-yl)imidazo[4,5-b]pyridin-2-yl]-diphenylmethanol	1782627: Inhibition of human recombinant ACSS2 assessed as AMP release using Coenzyme A/ATP as co-substrates by AMP Glo assay	ic50	<0.0001	uM
[1-ethyl-5-methoxy-6-(2H-tetrazol-5-yl)imidazo[4,5-b]pyridin-2-yl]-phenyl-thiophen-2-ylmethanol	1782628: Inhibition of ACSS2 in human HCT-15 cells assessed as inhibition of 14C acetate incorporation into fatty acids measured after 24 hrs by scintillation counting based cellular lipids assay	ic50	<0.0001	uM
6-chloro-3-ethyl-N-(1-ethyl-1,2,4-triazol-3-yl)-2-[hydroxy(diphenyl)methyl]pyrazolo[1,5-a]pyridine-5-carboxamide	1772177: Inhibition of human recombinant ACSS2 incubated for 180 mins by AMP Glo assay	ic50	<0.0001	uM
1-ethyl-N-(4-ethyl-1,3-oxazol-2-yl)-2-[hydroxy(diphenyl)methyl]-5-methoxyimidazo[4,5-b]pyridine-6-carboxamide	1772178: Inhibition of ACSS2 in human HCT-15 cells assessed as inhibition of 14C acetate incorporation into fatty acids by microbeta scintillation counting analysis	ic50	<0.0001	uM
[1-ethyl-5-methoxy-6-(2H-tetrazol-5-yl)imidazo[4,5-b]pyridin-2-yl]-phenyl-pyridin-2-ylmethanol	1782628: Inhibition of ACSS2 in human HCT-15 cells assessed as inhibition of 14C acetate incorporation into fatty acids measured after 24 hrs by scintillation counting based cellular lipids assay	ic50	<0.0001	uM
[1-ethyl-5-methoxy-6-(2H-tetrazol-5-yl)imidazo[4,5-b]pyridin-2-yl]-bis(2-fluorophenyl)methanol	1782627: Inhibition of human recombinant ACSS2 assessed as AMP release using Coenzyme A/ATP as co-substrates by AMP Glo assay	ic50	<0.0001	uM
1-ethyl-N-(1-ethyl-1,2,4-triazol-3-yl)-2-[hydroxy(dithiophen-2-yl)methyl]-5-methoxyimidazo[4,5-b]pyridine-6-carboxamide	1772178: Inhibition of ACSS2 in human HCT-15 cells assessed as inhibition of 14C acetate incorporation into fatty acids by microbeta scintillation counting analysis	ic50	<0.0001	uM
2-[bis(2-fluorophenyl)-hydroxymethyl]-1-ethyl-N-(1-ethyl-1,2,4-triazol-3-yl)-5-methoxyimidazo[4,5-b]pyridine-6-carboxamide	1772177: Inhibition of human recombinant ACSS2 incubated for 180 mins by AMP Glo assay	ic50	<0.0001	uM
1-ethyl-N-(5-ethyl-1,3-oxazol-2-yl)-2-[hydroxy(diphenyl)methyl]-5-methoxyimidazo[4,5-b]pyridine-6-carboxamide	1772177: Inhibition of human recombinant ACSS2 incubated for 180 mins by AMP Glo assay	ic50	<0.0001	uM
N-[3-(1,1-difluoroethyl)phenyl]-1-[4-(difluoromethoxy)-3-pyridin-3-ylphenyl]-3-methyl-5-oxo-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0003	uM
N-[3-(1,1-difluoropropyl)phenyl]-1-(4-methoxyphenyl)-3-methyl-5-oxo-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0005	uM
N-[3-(1,1-difluoroethyl)phenyl]-1-(3,4-dimethoxyphenyl)-3-methyl-5-oxo-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0010	uM
[1-ethyl-5-methoxy-6-(2H-tetrazol-5-yl)imidazo[4,5-b]pyridin-2-yl]-phenyl-pyrimidin-2-ylmethanol	1782627: Inhibition of human recombinant ACSS2 assessed as AMP release using Coenzyme A/ATP as co-substrates by AMP Glo assay	ic50	0.0010	uM
N-[3-(1,1-difluoroethyl)phenyl]-1-[4-methoxy-3-(1,3-oxazol-2-yl)phenyl]-3-methyl-5-oxo-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0011	uM
methyl 3-[4-[[3-(furan-2-yl)phenyl]carbamoyl]-3-methyl-5-oxo-4H-pyrazol-1-yl]benzoate	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0021	uM
N-[3-(1,1-difluoroethyl)phenyl]-1-[4-(difluoromethoxy)phenyl]-3-methyl-5-oxo-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0027	uM
N-[3-(furan-2-yl)phenyl]-1-(4-methoxyphenyl)-3-methyl-5-oxo-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0032	uM
N-[3-(furan-2-yl)phenyl]-1-(6-methoxy-3-pyridinyl)-3-methyl-5-oxo-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0039	uM
N-[3-(1,1-difluoroethyl)phenyl]-3-methyl-5-oxo-1-phenyl-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0040	uM
N-[3-(1,1-difluoroethyl)phenyl]-1-(4-methoxyphenyl)-3-methyl-5-oxo-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0045	uM
N-[3-(1,1-difluoroethyl)phenyl]-1-(6-methoxy-3-pyridinyl)-3-methyl-5-oxo-4H-pyrazole-4-carboxamide	1570321: Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	ic50	0.0050	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation, affects expression	4
Benzo(a)pyrene	decreases expression, increases methylation	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation	4
bisphenol A	affects expression, decreases methylation, increases expression	3
perfluorooctane sulfonic acid	decreases expression	3
Cisplatin	affects cotreatment, increases expression, decreases response to substance	3
Cyclosporine	increases expression, decreases expression	3
sodium arsenite	increases expression	2
cupric chloride	decreases expression	2
Dexamethasone	increases expression, affects cotreatment	2
Glucose	increases expression	2
Nickel	decreases expression	2
Oxygen	increases expression, affects expression	2
Ozone	decreases expression, increases oxidation, increases abundance, affects expression, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	decreases expression, decreases methylation, affects expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
aristolochic acid I	increases expression	1
afuresertib	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
methyleugenol	decreases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	decreases expression	1
dodecyldimethylamine oxide	increases expression	1
beta-lapachone	decreases expression	1
methylparaben	increases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4368259	Binding	Inhibition of ACSS2 in human MDA-MB-468 cells assessed as 13C-acetate incorporation incubated for 5 hrs measured under hypoxic conditions by LCMS analysis	Inhibition of ACSS2 for Treatment of Cancer and Neuropsychiatric Diseases. — ACS Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SB26	HAP1 ACSS2 (-) 1	Cancer cell line	Male
CVCL_XL00	HAP1 ACSS2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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