GLS

Summary

GLS (glutaminase, HGNC:4331) is a protein-coding gene on chromosome 2q32.2, encoding Glutaminase kidney isoform, mitochondrial (O94925). Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. It is a selective cancer dependency (DepMap: 10.3% of cell lines).

This gene encodes the K-type mitochondrial glutaminase. The encoded protein is an phosphate-activated amidohydrolase that catalyzes the hydrolysis of glutamine to glutamate and ammonia. This protein is primarily expressed in the brain and kidney plays an essential role in generating energy for metabolism, synthesizing the brain neurotransmitter glutamate and maintaining acid-base balance in the kidney. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 2744 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glutaminase deficiency (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 176 total — 9 pathogenic, 8 likely-pathogenic
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 10.3% of screened cell lines
• MANE Select transcript: NM_014905

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4331
Approved symbol	GLS
Name	glutaminase
Location	2q32.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0838, GLS1, GAC, GAM, KGA
Ensembl gene	ENSG00000115419
Ensembl biotype	protein_coding
OMIM	138280
Entrez	2744

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 8 protein_coding, 8 retained_intron, 2 nonsense_mediated_decay

ENST00000320717, ENST00000338435, ENST00000409215, ENST00000409428, ENST00000409626, ENST00000412247, ENST00000417154, ENST00000457316, ENST00000461965, ENST00000468352, ENST00000469774, ENST00000471443, ENST00000479552, ENST00000495444, ENST00000496170, ENST00000706565, ENST00000950145, ENST00000950146

RefSeq mRNA: 2 — MANE Select: NM_014905 NM_001256310, NM_014905

CCDS: CCDS2308, CCDS58744

Canonical transcript exons

ENST00000320717 — 18 exons

Exon	Start	End
ENSE00000883247	190905004	190905167
ENSE00000883250	190895604	190895725
ENSE00000934465	190931545	190931637
ENSE00000964752	190927306	190927482
ENSE00001261350	190954584	190954660
ENSE00001261357	190953565	190953626
ENSE00001261459	190962830	190965552
ENSE00001625075	190954755	190954818
ENSE00001906955	190880821	190881470
ENSE00003493355	190901947	190902026
ENSE00003507799	190895152	190895248
ENSE00003526870	190921145	190921203
ENSE00003565716	190930437	190930568
ENSE00003566558	190921024	190921056
ENSE00003632701	190924543	190924593
ENSE00003648403	190910263	190910321
ENSE00003656201	190900564	190900693
ENSE00003660871	190923917	190923983

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 96.9176 / max 1215.9933, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24318	89.0472	1825
24319	6.9274	1567
24326	0.3316	124
24321	0.2830	113
24324	0.2260	14
24317	0.1024	52

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	99.84	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.72	gold quality
pons	UBERON:0000988	99.50	gold quality
nephron tubule	UBERON:0001231	99.41	gold quality
calcaneal tendon	UBERON:0003701	99.33	gold quality
renal medulla	UBERON:0000362	99.16	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.16	gold quality
renal glomerulus	UBERON:0000074	99.10	gold quality
metanephric glomerulus	UBERON:0004736	99.10	gold quality
postcentral gyrus	UBERON:0002581	99.09	gold quality
parietal lobe	UBERON:0001872	99.06	gold quality
orbitofrontal cortex	UBERON:0004167	99.06	gold quality
adrenal tissue	UBERON:0018303	98.91	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.83	gold quality
endothelial cell	CL:0000115	98.65	gold quality
frontal pole	UBERON:0002795	98.55	gold quality
cortex of kidney	UBERON:0001225	98.47	gold quality
superior vestibular nucleus	UBERON:0007227	98.47	gold quality
adult organism	UBERON:0007023	98.46	gold quality
blood vessel layer	UBERON:0004797	98.41	gold quality
occipital lobe	UBERON:0002021	98.39	gold quality
superior frontal gyrus	UBERON:0002661	98.33	gold quality
substantia nigra pars compacta	UBERON:0001965	98.26	gold quality
primary visual cortex	UBERON:0002436	98.25	gold quality
entorhinal cortex	UBERON:0002728	98.22	gold quality
CA1 field of hippocampus	UBERON:0003881	98.02	gold quality
visceral pleura	UBERON:0002401	97.97	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.97	gold quality
jejunal mucosa	UBERON:0000399	97.89	gold quality
metanephros cortex	UBERON:0010533	97.88	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-GEOD-86618	yes	1793.69
E-GEOD-81608	yes	1622.77
E-GEOD-83139	yes	1384.84
E-ENAD-27	yes	1046.29
E-MTAB-5061	yes	932.52
E-HCAD-10	yes	35.98
E-HCAD-31	yes	31.96
E-CURD-119	yes	30.03
E-GEOD-81547	yes	19.95
E-GEOD-124858	no	2558.44
E-MTAB-10290	no	524.21
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

144 targeting GLS, 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-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-1277-5P	100.00	73.95	5056
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-4262	100.00	73.26	3931
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Data suggest that glutaminase is an important factor in melanoma cell proliferation. (PMID:12579526)
• human neutrophils appeared to utilize glutamine and posess the appropriate glutaminase enzyme for metabolizing glutamine. (PMID:14722097)
• possible role for intestinal glutaminase in the pathogenesis of hepatic encephalopathy (PMID:15246207)
• K glutaminase isoform is up-regulated with increased rates of proliferation in cancer cells, whereas prevalence of the L isoform seems to be related with resting or quiescent cell states (PMID:15496140)
• c-Myc transcriptionally represses miR-23a and miR-23b, resulting in greater expression of their target protein, mitochondrial glutaminase, in human P-493 B lymphoma cells and PC3 prostate cancer cells (PMID:19219026)
• Release of glutaminase from dysfunctional macrophages is a possible mechanism of glutaminase-mediated production of excitotoxic glutamate during the pathogenic process of human immunodeficiency virus (HIV)-1 associated dementia. (PMID:19222703)
• Glutaminase is considered as the main glutamate-producer enzyme in brain–REVIEW (PMID:19428808)
• this brief review summarizes available data on the expression profiles and activities of glutaminase isoenzymes in different neoplastic tissues–REVIEW (PMID:19428809)
• Multiple transcripts for glutaminase genes and simultaneous expression of glutaminase isoforms have been reported in mammalian tissues and cells–REVIEW (PMID:19428810)
• GA mRNA and protein expression was not different between normal and fetal growth restriction pregnancy (PMID:19500843)
• This study identifies mutations in the gene sequence for glutaminase that are associated with development of hepatic encephalopathy in patients with cirrhosis (PMID:20820037)
• Data show that the ability to selectively slow growth in cells with IDH1 mutations by inhibiting glutaminase suggesting a unique reprogramming of intermediary metabolism and a potential therapeutic strategy. (PMID:21045145)
• Glutaminase: a hot spot for regulation of cancer cell metabolism. (PMID:21234284)
• This studt demonistrated that the genetic variation in the glutaminase gene GLS1 is related the glutamine/glutamate ratio in brain. (PMID:21457947)
• Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia (PMID:21852960)
• first report of full-length crystal structure of a splice variant of GLS1 in presence/absence of BPTES, an allosteric inhibitor: 2 BPTES molecules bind at interface of GLS1 tetramer; appear to lock GLS1 tetramer into nonproductive conformation (PMID:22049910)
• GLS1 differs from PFKFB3 in that its recognition by APC/C-Cdh1 during S phase requires the presence of both a Lys-Glu-Asn box (KEN box) and a destruction box (D box) rather than a KEN box alone. (PMID:22106309)
• Inhibition of Gls1 kills lung cancer cells that overexpress MYC and catabolize glutamine. (PMID:22326218)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• Data indicate that both HIV-1 infection and IFN-alpha treatment increase glutaminase 1 (GLS1) expression through STAT1 phosphorylation and by binding to the GLS1 promoter. (PMID:22479354)
• KGA activity in cells is stimulated by EGF, and KGA associates with all three kinase components of the Raf-1/Mek2/Erk signaling module. (PMID:22538822)
• NSCLC cell lines depend on Gln for glutaminolysis to a varying degree, in which the GLS1 splice variant GAC plays an essential role and is a potential target for cancer metabolism-directed therapy. (PMID:22892846)
• HER2- type breast cancer had the highest expression of stromal GLS1, tumoral GDH, stromal GDH, and tumoral ASCT, while TNBC had the lowest tumoral GDH expression. (PMID:23507704)
• neuronal glutaminase is a potential component of neurotoxicity during inflammation and modulation of glutaminase may provide therapeutic avenues for neurodegenerative diseases. (PMID:23578284)
• stromal expression of the glutamine-metabolism-related proteins GLS1, GDH, ASCT2 increases with worsening histological phyllodes tumor grade. (PMID:23636801)
• A glutaminase inhibitor reduced conversion of (13)C-pyruvate to alanine. (PMID:23722553)
• activated glutaminase C (GAC) self-assembles into a helical, fiber-like double-stranded oligomer and propose a molecular model consisting of seven tetramer copies per turn per strand interacting via the N-terminal domains (PMID:23935106)
• STAT1 regulates human glutaminase 1 promoter activity (PMID:24086752)
• our data indicate that ErbB2 activation promotes GLS1 expression via a PI3K-Akt-independent NF-kappaB pathway in breast cancer cells, identifying another oncogenic signaling pathway which stimulates GLS1 expression (PMID:24122876)
• Silencing GLS or overexpressing GLS2 induces growth inhibition in glioma cell lines. (PMID:24276018)
• Inhibition of glutaminase selectively suppresses the growth of primary acute myeloid leukemia cells with IDH mutations. (PMID:24333121)
• These results suggest that the expression of GLS1 is upregulated and correlates with clinicopathological factors in colorectal cancer. (PMID:24696726)
• The rate of Glu decarboxylation into GABA by Glnase is an order of magnitude lower than that of Glutamate decarboxylase. Potential impact on the mechanistic aspects of Gln-Glu shuttle in neuroscience and glutaminolysis in tumors, is discussed. (PMID:24755074)
• GABAergic neurons and astrocytes express Gls and Gls2 isoenzymes in nucleus and mitochondria, in addition to glutamatergic neurons (PMID:25297978)
• GLS1 has a key role in coupling glutaminolysis of the TCA cycle with elevated glucose uptake and consequently the growth of prostate cancer cells (PMID:25482439)
• Our findings support the role of the GLS long microsatellite in the development of HE; this could be important for identifying susceptible patients and for the prevention of this condition. (PMID:25880019)
• studies demonstrate that GLS is required for tumorigenesis and support small molecule and genetic inhibition of GLS as potential approaches for targeting the tumor cell-autonomous dependence on GLS for cancer therapy. (PMID:25915584)
• In the present study it was determined whether three key enzymes for glycolysis, glutaminolysis and de novo synthesis of FAs, hexokinase-2, glutaminase and fatty acid synthase (PMID:26134042)
• Data suggest that glutaminase C (GAC) inhibition maybe a potential treatment strategy for acquired erlotinib-resistant non-small cell lung cancer (NSCLC). (PMID:26575584)
• GLS1 was identified as a potential downstream target of the miR-192/-204-HOTTIP axis in hepatocellular carcinoma. (PMID:26710269)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	glsb	ENSDARG00000040705
danio_rerio	glsa	ENSDARG00000062812
mus_musculus	Gls	ENSMUSG00000026103
rattus_norvegicus	Gls	ENSRNOG00000056246
drosophila_melanogaster	GLS	FBGN0261625
caenorhabditis_elegans		WBGENE00007480
caenorhabditis_elegans		WBGENE00008435
caenorhabditis_elegans	glna-3	WBGENE00009271

Paralogs (1): GLS2 (ENSG00000135423)

Protein

Protein identifiers

Glutaminase kidney isoform, mitochondrial — O94925 (reviewed: O94925)

Alternative names: K-glutaminase, L-glutamine amidohydrolase

All UniProt accessions (7): A0A994J3S8, A0A9L9PXA4, B7Z509, B8ZZC5, O94925, H7BZD1, H7C201

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain. Lacks catalytic activity.

Subunit / interactions. Homotetramer, dimer of dimers. The tetramers can assemble into rod-like oligomers (in vitro), but the physiological significance of this is not clear. Interacts with RAF1 and MAP2K2. Interacts with ATCAY; the interaction is direct and may control GLS localization, negatively regulating its activity.

Subcellular location. Mitochondrion. Cytoplasm. Cytosol Mitochondrion Mitochondrion matrix Mitochondrion matrix.

Tissue specificity. Isoform 1 and isoform 3 are detected in brain cortex. Isoform 3 is highly expressed in astrocytoma, ganglioglioma and ependymoma. Isoform 1 is highly expressed in brain and kidney, but not detected in liver. Isoform 3 is highly expressed in heart and pancreas, detected at lower levels in placenta, lung, pancreas and kidney, but is not detected in liver. Isoform 2 is expressed in cardiac and skeletal muscle.

Post-translational modifications. Synthesized as a 74-kDa cytosolic precursor which is proteolytically processed by the mitochondrial-processing peptidase (MPP) via a 72-kDa intermediate to yield the mature mitochondrial 68- and 65-kDa subunits.

Disease relevance. Developmental and epileptic encephalopathy 71 (DEE71) [MIM:618328] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE71 is an autosomal recessive form with onset at birth. Death occurs in first weeks of life. The disease is caused by variants affecting the gene represented in this entry. CASGID syndrome (CASGID) [MIM:618339] An autosomal dominant disease characterized by infantile-onset cataract, erythematic subcutaneous nodules, profound developmental delay, self-injurious behavior, and intracerebral glutamate excess. Histopathologic analysis of skin lesions show deep perivascular and periglandular lymphohistiocytic infiltrates and pronounced leukocytoclasia at the surface of the dermis, focal vacuolar alterations, hyperkeratosis, and parakeratosis of the epidermis. The disease is caused by variants affecting the gene represented in this entry. Global developmental delay, progressive ataxia, and elevated glutamine (GDPAG) [MIM:618412] An autosomal recessive disease characterized by early-onset delay in motor skills, delayed speech, progressive ataxia, and neurologic deterioration. Plasma glutamine is persistently elevated by a factor of 2.5 despite normal plasma ammonia levels. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Isoform 1 and isoform 3 are activated by phosphate. Inhibited by BPTES. BPTES binds between subunits and favors dissociation of the tetramer into dimers. Inhibited by 6-diazo-5-oxo-L-norleucine (DON). Enzyme activity is stimulated by phosphorylation.

Domain organisation. The C-terminal ANK repeats prevent the assembly of the supra-tetrameric filaments. A highly mobile activation loop at the dimer-dimer interface is important for enzyme activity.

Similarity. Belongs to the glutaminase family.

Isoforms (3)

UniProt ID	Names	Canonical?
O94925-1	1, KGA	yes
O94925-2	2, GAM
O94925-3	3, Glutaminase C, GAC

RefSeq proteins (2): NP_001243239, NP_055720* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR012338	Beta-lactam/transpept-like	Homologous_superfamily
IPR015868	Glutaminase	Family
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR041541	Glutaminase_EF-hand	Domain

Pfam: PF04960, PF12796, PF17959

Enzyme classification (BRENDA):

• EC 3.5.1.2 — glutaminase (BRENDA: 56 organisms, 201 substrates, 332 inhibitors, 107 Km, 53 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
L-GLUTAMINE	0.0053–460	51
GLN	0.42–21	12
L-ASPARAGINE	0.1–0.29	5
L-GLN	2.6–6.5	4
GLUTAMINE	4.8–109.5	3
2-OXO-SUCCINAMATE	0.003–0.017	2
GLUTARAMATE	1.27–1.48	2
L-ASN	4.8–24	2
L-GLUTAMIC ACID	5.13–500	2
SUCCINAMATE	0.14–0.23	2
2-OXO-GLUTARAMATE	0.195	1
5-METHOXY-2,5-DIOXOPENTANOIC ACID	0.012	1
D-GAMMA-GLN-METHYLESTER	6.7	1
D-GLUTAMINE	83	1
D-THEANINE	0.92	1

Catalyzed reactions (Rhea), 1 shown:

• L-glutamine + H2O = L-glutamate + NH4(+) (RHEA:15889)

UniProt features (98 total): helix 30, strand 19, mutagenesis site 10, binding site 7, sequence variant 5, turn 5, modified residue 4, sequence conflict 4, splice variant 3, region of interest 3, chain 2, repeat 2, compositionally biased region 2, transit peptide 1, site 1

Structure

Experimental structures (PDB)

50 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5U0I	X-RAY DIFFRACTION	1.42
5U0J	X-RAY DIFFRACTION	1.72
8JUB	X-RAY DIFFRACTION	2.01
5JYO	X-RAY DIFFRACTION	2.1
8BSK	X-RAY DIFFRACTION	2.1
7SBN	X-RAY DIFFRACTION	2.14
3VOY	X-RAY DIFFRACTION	2.2
3UO9	X-RAY DIFFRACTION	2.3
3VP1	X-RAY DIFFRACTION	2.3
4O7D	X-RAY DIFFRACTION	2.3
8BSL	X-RAY DIFFRACTION	2.38
8JUE	X-RAY DIFFRACTION	2.39
3CZD	X-RAY DIFFRACTION	2.4
3VOZ	X-RAY DIFFRACTION	2.4
3VP0	X-RAY DIFFRACTION	2.4
5HL1	X-RAY DIFFRACTION	2.4
5WJ6	X-RAY DIFFRACTION	2.44
3VP4	X-RAY DIFFRACTION	2.45
8BSN	X-RAY DIFFRACTION	2.49
5FI2	X-RAY DIFFRACTION	2.5
5FI7	X-RAY DIFFRACTION	2.5
6UJM	X-RAY DIFFRACTION	2.5
6UL9	X-RAY DIFFRACTION	2.5
5FI6	X-RAY DIFFRACTION	2.52
3UNW	X-RAY DIFFRACTION	2.56
6UMF	X-RAY DIFFRACTION	2.68
6ULJ	X-RAY DIFFRACTION	2.69
3VP2	X-RAY DIFFRACTION	2.7
3VP3	X-RAY DIFFRACTION	2.7
6UMD	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94925-F1	80.96	0.67

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): 72–73 (cleavage; by mpp)

Ligand- & substrate-binding residues (7): 286; 335; 381; 388; 414; 466; 484

Post-translational modifications (4): 130, 164, 311, 652

Mutagenesis-validated functional residues (10):

Position	Phenotype
249	loss of enzyme activity.
286	loss of enzyme activity.
289	loss of enzyme activity.
318	no effect on catalytic activity. loss of inhibition by bptes; when associated with s-322.
321	decreased enzyme activity.
322	no effect on catalytic activity. loss of inhibition by bptes; when associated with y-318.
323	decreased enzyme activity.
394	decreased enzyme activity.
394	no effect on catalytic activity. loss of inhibition by bptes.
466	loss of enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-210500	Glutamate Neurotransmitter Release Cycle
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-8964539	Glutamate and glutamine metabolism

MSigDB gene sets: 410 (showing top): HORIUCHI_WTAP_TARGETS_DN, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_BEHAVIOR, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_REGULATION_OF_RESPIRATORY_SYSTEM_PROCESS, GOBP_GLUTAMATE_METABOLIC_PROCESS, GOBP_SUCKLING_BEHAVIOR, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, BRUECKNER_TARGETS_OF_MIRLET7A3_DN

GO Biological Process (9): suckling behavior (GO:0001967), regulation of respiratory gaseous exchange by nervous system process (GO:0002087), obsolete glutamate biosynthetic process (GO:0006537), L-glutamine catabolic process (GO:0006543), chemical synaptic transmission (GO:0007268), protein homotetramerization (GO:0051289), intracellular glutamate homeostasis (GO:0090461), amino acid metabolic process (GO:0006520), L-glutamine metabolic process (GO:0006541)

GO Molecular Function (3): glutaminase activity (GO:0004359), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829), synapse (GO:0045202), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Neurotransmitter release cycle	1
Transcriptional Regulation by TP53	1
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
cellular anatomical structure	2
feeding behavior	1
respiratory gaseous exchange by respiratory system	1
regulation of respiratory system process	1
nervous system process	1
L-glutamine metabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
anterograde trans-synaptic signaling	1
protein homooligomerization	1
protein tetramerization	1
intracellular amino acid homeostasis	1
primary metabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
cell junction	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1482 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLS	AGA	P20933	836
GLS	SLC1A5	Q15758	800
GLS	GLUD1	P00367	736
GLS	GLUL	P15104	717
GLS	GGCT	O75223	701
GLS	IDH1	O75874	694
GLS	LDHA	P00338	605
GLS	GLYAT	Q6IB77	574
GLS	ASS1	P00966	571
GLS	MYC	P01106	571
GLS	ASNS	P08184	542
GLS	PKM	P14618	536
GLS	SLC7A5	Q01650	532
GLS	CHM	P24386	532
GLS	SLC7A11	Q9UPY5	531

IntAct

145 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
GLS2	HIP1	psi-mi:“MI:0914”(association)	0.670
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
TNF	B4GALT5	psi-mi:“MI:0914”(association)	0.530
CCL22	PLXNA2	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
TRMT61B	GLS	psi-mi:“MI:0914”(association)	0.480
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
SIRT5	GLS	psi-mi:“MI:0403”(colocalization)	0.460
SIRT5	GLS	psi-mi:“MI:0915”(physical association)	0.460
GLS	GLS	psi-mi:“MI:0407”(direct interaction)	0.440
AIFM1	HAX1	psi-mi:“MI:2364”(proximity)	0.420
AIFM1	SEC16A	psi-mi:“MI:2364”(proximity)	0.420
TUBA1A	TUBAL3	psi-mi:“MI:2364”(proximity)	0.420
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
	GLS	psi-mi:“MI:0915”(physical association)	0.400
KLHL13	GLS	psi-mi:“MI:0915”(physical association)	0.400
PRPF8	GLS	psi-mi:“MI:0915”(physical association)	0.400
MTUS1	GLS	psi-mi:“MI:0915”(physical association)	0.400
	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
FASTKD3	VWA8	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
CUL5	DDX3X	psi-mi:“MI:0914”(association)	0.350

BioGRID (275): GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-MS), GLS (Affinity Capture-RNA), GLS (Affinity Capture-Western)

ESM2 similar proteins: A0A2R8QFQ6, A0A2R8RWN9, D3Z7P3, E9PV86, G3MWR8, O54865, O60907, O89050, O94925, P13264, P16068, P20595, P58058, Q02153, Q08211, Q12800, Q13042, Q14722, Q28141, Q28D01, Q3MHJ2, Q3ULA2, Q4R8H1, Q4ZHR9, Q5R874, Q5RB35, Q5SP67, Q5SRY7, Q5ZHN3, Q6DN14, Q7RTP6, Q7T2U9, Q7Z6J6, Q8BTG7, Q8C6G8, Q8CJ19, Q8K4Q0, Q8N122, Q8N2K0, Q8R349

Diamond homologs: A0KNV3, A0PTH3, A4IPX2, A4SJB3, A4WAF3, A5CLW1, A5F9H5, A5I5P4, A5VA34, A6LA76, A6T8Z6, A6TU96, A7FX54, A7GH26, A7MPS3, A7MTN6, A8EX66, A8IEU9, A8MIB3, A9ME88, A9MRQ5, A9W5B4, A9WY35, B0C9Y4, B0JPM4, B0UQS5, B1IKM0, B1KYY3, B1LUS0, B1Z987, B2HGL4, B2SBQ3, B2TG13, B2UL96, B3PPT2, B3QKT6, B5QTS1, B5XQU9, B5ZRF0, B6EMU2

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
GLS	“up-regulates activity”	Glutaminolysis
GLS	“down-regulates quantity”	“L-glutamine zwitterion”	“chemical modification”
SIRT5	“up-regulates activity”	GLS	binding
GLS	“up-regulates quantity”	L-glutamate(1-)	“chemical modification”
JUN	“up-regulates quantity by expression”	GLS	“transcriptional regulation”
MYC	“up-regulates quantity by expression”	GLS	“transcriptional regulation”
PPARG	“down-regulates quantity by repression”	GLS	“transcriptional regulation”
PRKCE	“up-regulates activity”	GLS	phosphorylation
miR-23a	“down-regulates quantity”	GLS	“post transcriptional regulation”
miR-23b	“down-regulates quantity”	GLS	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 162 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial protein import	7	10.8×	8e-04
Complex IV assembly	5	10.5×	8e-03
Complex I biogenesis	6	9.1×	5e-03
Respiratory electron transport	10	8.7×	9e-05
Mitochondrial ribosome-associated quality control	7	7.9×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	5	34.2×	2e-04
mitochondrial electron transport, NADH to ubiquinone	6	14.8×	1e-03
mitochondrial translation	8	9.6×	9e-04
mitochondrion organization	8	8.4×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	8
Uncertain significance	94
Likely benign	34
Benign	5

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1526059	NM_014905.5(GLS):c.1460dup (p.Ile488fs)	Pathogenic
3364564	NM_014905.5(GLS):c.671_681del (p.Phe224fs)	Pathogenic
3601004	NM_014905.5(GLS):c.1382A>T (p.His461Leu)	Pathogenic
618996	NM_014905.5(GLS):c.695dup (p.Asp232fs)	Pathogenic
618997	NM_014905.5(GLS):c.241C>T (p.Gln81Ter)	Pathogenic
618998	NM_014905.5(GLS):c.815G>A (p.Arg272Lys)	Pathogenic
619106	NM_014905.5(GLS):c.1445C>G (p.Ser482Cys)	Pathogenic
626334	NM_014905.5(GLS):c.938C>T (p.Pro313Leu)	Pathogenic
626336	NM_014905.5(GLS):c.923dup (p.Tyr308Ter)	Pathogenic
1068386	NM_014905.5(GLS):c.1072-2A>C	Likely pathogenic
1256052	NM_014905.5(GLS):c.866A>T (p.Lys289Ile)	Likely pathogenic
2440527	NM_014905.5(GLS):c.338_339dup (p.Ala114fs)	Likely pathogenic
2500264	NM_014905.5(GLS):c.1270T>C (p.Cys424Arg)	Likely pathogenic
3520672	NM_014905.5(GLS):c.1709G>A (p.Arg570Gln)	Likely pathogenic
4795756	NM_014905.5(GLS):c.637C>T (p.Gln213Ter)	Likely pathogenic
4812900	NM_014905.5(GLS):c.386+2T>C	Likely pathogenic
916560	NM_014905.5(GLS):c.1940C>T (p.Thr647Ile)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4380 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:190895193:T:C	L143P	1.000
2:190895195:T:C	F144L	1.000
2:190895197:C:A	F144L	1.000
2:190895197:C:G	F144L	1.000
2:190895241:T:C	F159S	1.000
2:190895608:T:C	L163P	1.000
2:190895620:G:A	G167E	1.000
2:190895623:T:C	L168S	1.000
2:190895641:G:C	R174T	1.000
2:190895641:G:T	R174M	1.000
2:190895719:T:C	F200S	1.000
2:190900590:T:C	L211S	1.000
2:190902011:C:A	T267K	1.000
2:190902020:G:A	G270E	1.000
2:190905126:C:A	P313Q	1.000
2:190905128:A:C	S314R	1.000
2:190905130:T:A	S314R	1.000
2:190905130:T:G	S314R	1.000
2:190905131:G:A	G315R	1.000
2:190905131:G:C	G315R	1.000
2:190905132:G:A	G315E	1.000
2:190905140:T:A	F318I	1.000
2:190905140:T:C	F318L	1.000
2:190905140:T:G	F318V	1.000
2:190905141:T:C	F318S	1.000
2:190905141:T:G	F318C	1.000
2:190905142:C:A	F318L	1.000
2:190905142:C:G	F318L	1.000
2:190905145:C:A	N319K	1.000
2:190905145:C:G	N319K	1.000

dbSNP variants (sampled 300 via entrez): RS1000004237 (2:190912062 C>G), RS1000038358 (2:190902172 A>T), RS1000050307 (2:190958539 T>A,C), RS1000057296 (2:190895607 C>T), RS1000071047 (2:190901764 A>C,G), RS1000105374 (2:190965041 G>A), RS1000117048 (2:190918352 C>T), RS1000130929 (2:190880091 TA>T), RS1000137833 (2:190965354 T>C), RS1000160785 (2:190939357 C>G), RS1000171262 (2:190919259 G>A,T), RS1000197206 (2:190893733 T>A), RS1000222497 (2:190963440 T>C), RS1000226173 (2:190879805 T>C), RS1000229236 (2:190939618 A>C)

Disease associations

OMIM: gene MIM:138280 | disease phenotypes: MIM:618339, MIM:618328, MIM:618412, MIM:189960

GenCC curated gene-disease

Disease	Classification	Inheritance
glutaminase deficiency	Definitive	Autosomal recessive
developmental and epileptic encephalopathy, 71	Strong	Autosomal recessive
infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development	Strong	Autosomal dominant
global developmental delay, progressive ataxia, and elevated glutamine	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
glutaminase deficiency	Definitive	AR
infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development	Limited	AD

Mondo (5): infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development (MONDO:0032685), developmental and epileptic encephalopathy, 71 (MONDO:0032678), global developmental delay, progressive ataxia, and elevated glutamine (MONDO:0032733), esophageal atresia/tracheoesophageal fistula (MONDO:0008586), glutaminase deficiency (MONDO:0600001)

Orphanet (2): Neonatal epileptic encephalopathy due to glutaminase deficiency (Orphanet:557064), Esophageal atresia (Orphanet:1199)

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST004032_11	JT interval (sulfonylurea treatment interaction)	5.000000e-08
GCST004628_151	Immature fraction of reticulocytes	5.000000e-11
GCST007576_206	Chronotype	1.000000e-09
GCST90000025_834	Appendicular lean mass	6.000000e-12
GCST90002385_456	High light scatter reticulocyte count	4.000000e-25
GCST90002386_270	High light scatter reticulocyte percentage of red cells	9.000000e-24
GCST90002387_271	Immature fraction of reticulocytes	6.000000e-24
GCST90002405_144	Reticulocyte count	9.000000e-18
GCST90002406_63	Reticulocyte fraction of red cells	9.000000e-17
GCST90020025_1743	Waist-to-hip ratio adjusted for BMI	3.000000e-08
GCST90020027_448	Waist-hip index	2.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007885	JT interval
EFO:0007922	response to sulfonylurea
EFO:0007986	reticulocyte count
EFO:0008328	chronotype measurement
EFO:0004980	appendicular lean mass
EFO:0007788	BMI-adjusted waist-hip ratio

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C531835	Esophageal atresia with or without tracheoesophageal fistula (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2146302 (SINGLE PROTEIN), CHEMBL4106183 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,253 (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
CHEMBL3639788	TELAGLENASTAT	2	1,142
CHEMBL4741924	IPN-60090	1	111

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 3.5.1.2 Glutaminases

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

Ligand	Action	Affinity	Parameter
telaglenastat	Inhibition	8.3	pIC50
IPN60090	Inhibition	7.51	pIC50

Binding affinities (BindingDB)

729 measured of 1504 human assays (1504 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]methyl]benzamide	IC50	2 nM	US-8604016: Heterocyclic inhibitors of glutaminase
3-methyl-N-[[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]methyl]butanamide	IC50	2 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]methyl]-2-phenylacetamide	IC50	2 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-(2-oxo-2-pyrrolidin-1-ylethyl)phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	2 nM	US-8604016: Heterocyclic inhibitors of glutaminase
6-bromo-N-[[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]methyl]pyridazine-3-carboxamide	IC50	2 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[5-[4-[6-[[2-[3-(butylsulfonylmethyl)phenyl]acetyl]amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]-2-phenylacetamide	IC50	2 nM	US-8604016: Heterocyclic inhibitors of glutaminase
ethyl N-[[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]methyl]carbamate	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
ethyl N-[[3-[2-oxo-2-[[6-[4-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]amino]ethyl]phenyl]methyl]carbamate	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[[methyl-(2-phenylacetyl)amino]methyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-(3-acetamidophenyl)acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[(ethylcarbamoylamino)methyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[2-[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]ethyl]benzamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
ethyl 2-[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]acetate	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
2,2,2-trifluoro-N-[[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]methyl]acetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-(2-methylpropylamino)-2-oxoethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-(2,2-dimethylpropylamino)-2-oxoethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-[methyl(propyl)amino]-2-oxoethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-(butylamino)-2-oxoethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-[methyl(propan-2-yl)amino]-2-oxoethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[5-[8-amino-8-[2-[3-[2-(butylamino)-2-oxoethyl]phenyl]acetyl]imino-5-iminooctyl]-1,3,4-thiadiazol-2-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[5-[8-amino-5-imino-8-[2-[3-[2-(2-methylpropylamino)-2-oxoethyl]phenyl]acetyl]iminooctyl]-1,3,4-thiadiazol-2-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
ethyl N-[1-[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]ethyl]carbamate	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
ethyl N-[[3-[2-[[5-[4-[6-[[2-[3-[(ethoxycarbonylamino)methyl]phenyl]acetyl]amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]-2-oxoethyl]phenyl]methyl]carbamate	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
2-(4-hydroxyphenyl)-N-[[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]methyl]propanamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[5-[8-amino-5-imino-8-[2-[3-(3-methylsulfonylpropoxy)phenyl]acetyl]iminooctyl]-1,3,4-thiadiazol-2-yl]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[1-amino-8-[5-[[2-[3-(butylsulfonylmethyl)phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]-4-iminooctylidene]-2-phenylacetamide	IC50	3 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[5-[(5Z,7E)-5,8-diamino-8-[[2-[3-[2-(butylamino)-2-oxoethyl]phenyl]acetyl]amino]octa-5,7-dienyl]-1,3,4-thiadiazol-2-yl]-2-phenylacetamide	IC50	3 nM	US-9938267: Heterocyclic inhibitors of glutaminase
N-[5-[(5Z,7E)-5,8-diamino-8-[[2-[3-[2-(2-methylpropylamino)-2-oxoethyl]phenyl]acetyl]amino]octa-5,7-dienyl]-1,3,4-thiadiazol-2-yl]-2-phenylacetamide	IC50	3 nM	US-9938267: Heterocyclic inhibitors of glutaminase
N-[5-[(5Z,7E)-5,8-diamino-8-[[2-[3-(3-methylsulfonylpropoxy)phenyl]acetyl]amino]octa-5,7-dienyl]-1,3,4-thiadiazol-2-yl]-2-phenylacetamide	IC50	3 nM	US-9938267: Heterocyclic inhibitors of glutaminase
N-[(1E,3Z)-1,4-diamino-8-[5-[[2-[3-(butylsulfonylmethyl)phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]octa-1,3-dienyl]-2-phenylacetamide	IC50	3 nM	US-9938267: Heterocyclic inhibitors of glutaminase
2-phenyl-N-[6-[4-[5-[[2-[3-(pyrazol-1-ylmethyl)phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]acetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
tert-butyl N-methyl-N-[[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]methyl]carbamate	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-(3,5-dimethoxyphenyl)acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
tert-butyl N-[2-[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]ethyl]carbamate	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[[acetyl(methyl)amino]methyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-(methanesulfonamidomethyl)phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[(2-oxopiperidin-1-yl)methyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-(3,3-dimethylpyrrolidin-1-yl)-2-oxoethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-[butyl(methyl)amino]-2-oxoethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-[methyl(2-methylpropyl)amino]-2-oxoethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-[ethyl(methyl)amino]-2-oxoethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-[3-[2-oxo-2-(propylamino)ethyl]phenyl]acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
2-phenyl-N-[5-[4-[6-[[2-[3-(pyrazol-1-ylmethyl)phenyl]acetyl]amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]acetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
ethyl 2-[3-[2-oxo-2-[[6-[4-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]amino]ethyl]phenyl]acetate	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[5-[8-amino-5-imino-8-[2-[3-[(2-methylimidazol-1-yl)methyl]phenyl]acetyl]iminooctyl]-1,3,4-thiadiazol-2-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[6-[4-[5-[[2-(4-fluoro-3-hydroxyphenyl)acetyl]amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
tert-butyl N-[1-[3-[2-oxo-2-[[5-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]amino]ethyl]phenyl]ethyl]carbamate	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
N-[5-[4-[6-[[2-[3-[2-(tert-butylamino)-2-oxoethyl]phenyl]acetyl]amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]-2-phenylacetamide	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase
tert-butyl N-[1-[3-[2-oxo-2-[[6-[4-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]amino]ethyl]phenyl]ethyl]carbamate	IC50	4 nM	US-8604016: Heterocyclic inhibitors of glutaminase

ChEMBL bioactivities

2417 potent at pChembl≥5 of 2490 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL4538736
9.70	IC50	0.2	nM	CHEMBL4547874
9.69	IC50	0.206	nM	CHEMBL3810168
9.41	IC50	0.39	nM	CHEMBL3810394
9.40	IC50	0.4006	nM	CHEMBL3809014
9.30	IC50	0.5	nM	CHEMBL4454263
9.00	IC50	1	nM	CHEMBL4469040
9.00	IC50	1	nM	CHEMBL4475144
8.70	IC50	2	nM	CHEMBL3680041
8.70	IC50	2	nM	CHEMBL3675017
8.70	IC50	2	nM	CHEMBL3675018
8.70	IC50	2	nM	CHEMBL3675020
8.70	IC50	2	nM	CHEMBL3675057
8.70	IC50	2	nM	CHEMBL3675059
8.70	IC50	2	nM	TELAGLENASTAT
8.70	IC50	2	nM	CHEMBL3670064
8.57	IC50	2.7	nM	CHEMBL4462146
8.52	IC50	3	nM	CHEMBL3674968
8.52	IC50	3	nM	CHEMBL3674970
8.52	IC50	3	nM	CHEMBL3675029
8.52	IC50	3	nM	CHEMBL3675036
8.52	IC50	3	nM	CHEMBL3675038
8.52	IC50	3	nM	CHEMBL3675040
8.52	IC50	3	nM	CHEMBL3675041
8.52	IC50	3	nM	CHEMBL3675043
8.52	IC50	3	nM	CHEMBL3675054
8.52	IC50	3	nM	CHEMBL3675055
8.52	IC50	3	nM	CHEMBL3675058
8.52	IC50	3	nM	CHEMBL3675067
8.52	IC50	3	nM	CHEMBL3675079
8.52	IC50	3	nM	CHEMBL3675081
8.52	IC50	3	nM	CHEMBL3675099
8.52	IC50	3	nM	CHEMBL3675100
8.52	IC50	3	nM	CHEMBL3675140
8.52	IC50	3	nM	CHEMBL3675141
8.52	IC50	3	nM	CHEMBL3675150
8.52	IC50	3	nM	CHEMBL3675153
8.52	IC50	3	nM	CHEMBL3679964
8.52	IC50	3	nM	CHEMBL3679978
8.52	IC50	3	nM	CHEMBL5883747
8.52	IC50	3	nM	CHEMBL5825833
8.52	IC50	3	nM	CHEMBL5968505
8.52	IC50	3	nM	CHEMBL6039931
8.41	IC50	3.9	nM	CHEMBL3808443
8.40	IC50	4	nM	CHEMBL3674980
8.40	IC50	4	nM	CHEMBL3674981
8.40	IC50	4	nM	CHEMBL3674983
8.40	IC50	4	nM	CHEMBL3675014
8.40	IC50	4	nM	CHEMBL3675030
8.40	IC50	4	nM	CHEMBL3675037

PubChem BioAssay actives

540 with measured affinity, of 904 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[6-[[(1R,3S)-3-[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl]cyclopentyl]methyl]pyridazin-3-yl]-2-[3-(trifluoromethoxy)phenyl]acetamide	1513143: Inhibition of kidney-type glutaminase in human BT20 cells assessed as reduction in glutamate level	ic50	0.0001	uM
N-[6-[[3-[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl]cyclobutyl]methyl]pyridazin-3-yl]-2-[3-(trifluoromethoxy)phenyl]acetamide	1513143: Inhibition of kidney-type glutaminase in human BT20 cells assessed as reduction in glutamate level	ic50	0.0002	uM
(2R)-2-methoxy-N-[5-[[(3R)-1-(1,2,4-triazin-6-yl)pyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]-2-[3-(trifluoromethoxy)phenyl]acetamide	1301594: Inhibition of GLS1 in human PC3 cells assessed as cellular glutamate depletion levels after 6 hrs by Glutamate Oxidase/ AmplexRed coupled assay	ic50	0.0002	uM
(2S)-2-methoxy-2-phenyl-N-[5-[[(3R)-1-(1,2,4-triazin-6-yl)pyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]acetamide	1301594: Inhibition of GLS1 in human PC3 cells assessed as cellular glutamate depletion levels after 6 hrs by Glutamate Oxidase/ AmplexRed coupled assay	ic50	0.0004	uM
(2S)-2-methoxy-2-(4-methoxyphenyl)-N-[5-[[(3R)-1-pyridazin-3-ylpyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]acetamide	1301594: Inhibition of GLS1 in human PC3 cells assessed as cellular glutamate depletion levels after 6 hrs by Glutamate Oxidase/ AmplexRed coupled assay	ic50	0.0004	uM
2-(1-methylpyrazol-3-yl)-N-[5-[2-[5-[[2-(1-methylpyrazol-3-yl)acetyl]amino]-1,3,4-thiadiazol-2-yl]spiro[3.3]heptan-6-yl]-1,3,4-thiadiazol-2-yl]acetamide	1513143: Inhibition of kidney-type glutaminase in human BT20 cells assessed as reduction in glutamate level	ic50	0.0005	uM
N-[6-[4-[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-selenadiazol-2-yl]butyl]pyridazin-3-yl]-2-[3-(trifluoromethoxy)phenyl]acetamide	1571774: Inhibition of human KGA preincubated for 15 to 30 mins followed by substrate addition and measured after 3 to 4 hrs by GDH-EZMTT reagent-based GDH coupled assay	ic50	0.0010	uM
N-[6-[4-[5-[[2-(1-methylindol-3-yl)acetyl]amino]-1,3,4-selenadiazol-2-yl]butyl]pyridazin-3-yl]-2-[3-(trifluoromethoxy)phenyl]acetamide	1571774: Inhibition of human KGA preincubated for 15 to 30 mins followed by substrate addition and measured after 3 to 4 hrs by GDH-EZMTT reagent-based GDH coupled assay	ic50	0.0010	uM
N-[6-[4-[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl]butyl]pyridazin-3-yl]-2-[3-(trifluoromethoxy)phenyl]acetamide	1571774: Inhibition of human KGA preincubated for 15 to 30 mins followed by substrate addition and measured after 3 to 4 hrs by GDH-EZMTT reagent-based GDH coupled assay	ic50	0.0020	uM
(2S)-2-methoxy-2-phenyl-N-[5-[[(3R)-1-(1,2,4-triazin-3-yl)pyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]acetamide	1301594: Inhibition of GLS1 in human PC3 cells assessed as cellular glutamate depletion levels after 6 hrs by Glutamate Oxidase/ AmplexRed coupled assay	ic50	0.0039	uM
N-[5-[4-[[5-[[(2R)-2-methoxy-2-phenylacetyl]amino]-1,3,4-thiadiazol-2-yl]amino]piperidin-1-yl]-1,3,4-thiadiazol-2-yl]-3-[1-[[4-(trifluoromethyl)cyclohexa-1,3-dien-1-yl]methyl]triazol-4-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0049	uM
(2R)-2-(4-fluoro-3-methoxyphenyl)-2-methoxy-N-[5-[[(3R)-1-(1,2,4-triazin-6-yl)pyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]acetamide	1301594: Inhibition of GLS1 in human PC3 cells assessed as cellular glutamate depletion levels after 6 hrs by Glutamate Oxidase/ AmplexRed coupled assay	ic50	0.0050	uM
1-[4-[6-[(2-pyridin-2-ylacetyl)amino]pyridazin-3-yl]butyl]-N-[[3-(trifluoromethoxy)phenyl]methyl]triazole-4-carboxamide	1681955: Inhibition of recombinant human GLS1 using glutamine as substrate preincubated for 10 mins followed by substrate addition and measured after 20 mins by glutamate oxidase/horseradish peroxidase-coupled Amplex UltraRED reagent based fluorescence assay	ic50	0.0060	uM
(2R)-2-methoxy-2-[3-methoxy-5-(trifluoromethoxy)phenyl]-N-[5-[[(3R)-1-pyridazin-3-ylpyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]acetamide	1513144: Inhibition of human KGA (63 to 669 residues) preincubated for 15 mins using 50 mM glutamine as substrate by resorufin dye based assay	ic50	0.0060	uM
(2S)-2-methoxy-2-[3-methoxy-5-(trifluoromethoxy)phenyl]-N-[5-[[(3R)-1-pyridazin-3-ylpyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]acetamide	1513144: Inhibition of human KGA (63 to 669 residues) preincubated for 15 mins using 50 mM glutamine as substrate by resorufin dye based assay	ic50	0.0060	uM
(13E)-10,17-dioxa-39-thia-2,25,27,28,35,36-hexazapentacyclo[32.2.2.15,9.118,22.126,29]hentetraconta-1(36),5(41),6,8,13,18,20,22(40),26,28,34,37-dodecaene-3,24-dione	1772184: Inhibition of recombinant human GLS1 expressed in Escherichia coli strain BL21 (DE3) preincubated for 10 mins before glutamine addition and measured after 60 mins by bovine liver glutamate dehydrogenase based coupled enzyme assay	ic50	0.0060	uM
2-(oxan-4-yl)-N-[5-[(3R)-3-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]pyrrolidin-1-yl]-1,3,4-thiadiazol-2-yl]acetamide	1562514: Inhibition of recombinant 6His-tagged GLS1 KGA isoform (unknown origin) (63 to 669 residues) expressed in Escherichia coli using glutamine as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by amplex red staining-based horseradish peroxidase/glutamate oxidase coupled assay	ic50	0.0070	uM
N-[5-[[1-[6-[[2-(3-butoxyphenyl)acetyl]amino]pyridazin-3-yl]piperidin-4-yl]amino]-1,3,4-thiadiazol-2-yl]pentanamide	2002512: Inhibition of GLS1 (unknown origin) preincubated for 10 mins followed by glutamine addition measured after 60 mins	ic50	0.0070	uM
2-phenyl-N-[5-[[(1R,2R)-2-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]cyclopentyl]amino]-1,3,4-thiadiazol-2-yl]acetamide	1562514: Inhibition of recombinant 6His-tagged GLS1 KGA isoform (unknown origin) (63 to 669 residues) expressed in Escherichia coli using glutamine as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by amplex red staining-based horseradish peroxidase/glutamate oxidase coupled assay	ic50	0.0080	uM
N-[5-[4-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]piperidin-1-yl]-1,3,4-thiadiazol-2-yl]-3-[1-[[4-(trifluoromethyl)phenyl]methyl]triazol-4-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0087	uM
3-[1-[(4-methylphenyl)methyl]triazol-4-yl]-N-[6-[(3R)-3-[[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]pyrrolidin-1-yl]pyridazin-3-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0089	uM
N-methyl-1-[4-[6-[[2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridinyl]acetyl]amino]pyridazin-3-yl]butyl]triazole-4-carboxamide	1681955: Inhibition of recombinant human GLS1 using glutamine as substrate preincubated for 10 mins followed by substrate addition and measured after 20 mins by glutamate oxidase/horseradish peroxidase-coupled Amplex UltraRED reagent based fluorescence assay	ic50	0.0100	uM
1-[(2R)-2-fluoro-4-[6-[[2-[4-[3-(trifluoromethoxy)phenyl]-2-pyridinyl]acetyl]amino]pyridazin-3-yl]butyl]-N-methyltriazole-4-carboxamide	1681955: Inhibition of recombinant human GLS1 using glutamine as substrate preincubated for 10 mins followed by substrate addition and measured after 20 mins by glutamate oxidase/horseradish peroxidase-coupled Amplex UltraRED reagent based fluorescence assay	ic50	0.0100	uM
N-[6-[4-[5-[[2-(5-methoxy-1-methylindol-3-yl)acetyl]amino]-1,3,4-selenadiazol-2-yl]butyl]pyridazin-3-yl]-2-[3-(trifluoromethoxy)phenyl]acetamide	1571774: Inhibition of human KGA preincubated for 15 to 30 mins followed by substrate addition and measured after 3 to 4 hrs by GDH-EZMTT reagent-based GDH coupled assay	ic50	0.0100	uM
N-[5-[4-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]oxy]piperidin-1-yl]-1,3,4-thiadiazol-2-yl]cyclopropanecarboxamide	1601274: Inhibition of recombinant human His-tagged GAC (72 to 603 residues) expressed in Escherichia coli using glutamine as substrate incubated for 10 mins	ic50	0.0100	uM
(2S)-2-phenyl-N-[5-[[(3R)-1-pyridazin-3-ylpyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]propanamide	1562514: Inhibition of recombinant 6His-tagged GLS1 KGA isoform (unknown origin) (63 to 669 residues) expressed in Escherichia coli using glutamine as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by amplex red staining-based horseradish peroxidase/glutamate oxidase coupled assay	ic50	0.0100	uM
2-phenyl-N-[6-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]pyridazin-3-yl]acetamide	1513134: Inhibition of GAC (unknown origin) assessed as NADH formation using 10 mM glutamine as substrate preincubated for 60 mins	ic50	0.0100	uM
N-[6-[(3R)-3-[[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]pyrrolidin-1-yl]pyridazin-3-yl]-3-[1-[[4-(trifluoromethyl)phenyl]methyl]triazol-4-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0103	uM
3-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]-N-[6-[(3R)-3-[[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]pyrrolidin-1-yl]pyridazin-3-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0113	uM
N-[5-[4-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]piperidin-1-yl]-1,3,4-thiadiazol-2-yl]-1-[[4-(trifluoromethyl)phenyl]methyl]imidazole-2-carboxamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0119	uM
3-[1-[(4-methylphenyl)methyl]triazol-4-yl]-N-[5-[4-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]piperidin-1-yl]-1,3,4-thiadiazol-2-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0124	uM
N-[5-[(3R)-3-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]pyrrolidin-1-yl]-1,3,4-thiadiazol-2-yl]-3-[1-[[4-(trifluoromethyl)phenyl]methyl]triazol-4-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0124	uM
N-[6-[(3R)-3-[[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]pyrrolidin-1-yl]pyridazin-3-yl]-3-[1-[[4-(trifluoromethoxy)phenyl]methyl]triazol-4-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0137	uM
N-benzyl-1-[4-[6-[(2-phenylacetyl)amino]pyridazin-3-yl]butyl]triazole-4-carboxamide	1681955: Inhibition of recombinant human GLS1 using glutamine as substrate preincubated for 10 mins followed by substrate addition and measured after 20 mins by glutamate oxidase/horseradish peroxidase-coupled Amplex UltraRED reagent based fluorescence assay	ic50	0.0140	uM
N-(pyridin-2-ylmethyl)-1-[4-[6-[[2-[3-(trifluoromethoxy)phenyl]acetyl]amino]pyridazin-3-yl]butyl]triazole-4-carboxamide	1681955: Inhibition of recombinant human GLS1 using glutamine as substrate preincubated for 10 mins followed by substrate addition and measured after 20 mins by glutamate oxidase/horseradish peroxidase-coupled Amplex UltraRED reagent based fluorescence assay	ic50	0.0140	uM
N-(cyanomethyl)-1-[4-[6-[[2-[3-(trifluoromethoxy)phenyl]acetyl]amino]pyridazin-3-yl]butyl]triazole-4-carboxamide	1681955: Inhibition of recombinant human GLS1 using glutamine as substrate preincubated for 10 mins followed by substrate addition and measured after 20 mins by glutamate oxidase/horseradish peroxidase-coupled Amplex UltraRED reagent based fluorescence assay	ic50	0.0140	uM
2-phenyl-N-[5-[[(3R)-1-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]pyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]acetamide	1562514: Inhibition of recombinant 6His-tagged GLS1 KGA isoform (unknown origin) (63 to 669 residues) expressed in Escherichia coli using glutamine as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by amplex red staining-based horseradish peroxidase/glutamate oxidase coupled assay	ic50	0.0140	uM
2-phenyl-N-[5-[[(3R)-1-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]pyrrolidin-3-yl]methylamino]-1,3,4-thiadiazol-2-yl]acetamide	1562514: Inhibition of recombinant 6His-tagged GLS1 KGA isoform (unknown origin) (63 to 669 residues) expressed in Escherichia coli using glutamine as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by amplex red staining-based horseradish peroxidase/glutamate oxidase coupled assay	ic50	0.0140	uM
3-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]-N-[5-[4-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]piperidin-1-yl]-1,3,4-thiadiazol-2-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0147	uM
1-[(2R)-4-[6-[[2-[4-(3,3-difluorocyclobutyl)oxy-6-methyl-2-pyridinyl]acetyl]amino]pyridazin-3-yl]-2-fluorobutyl]-N-methyltriazole-4-carboxamide	1681957: Inhibition of GLS1 in human A549 cells assessed as reduction in conversion of glutamine to glutamate measured after 24 hrs	ic50	0.0160	uM
2-phenyl-N-[5-[2-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]ethylamino]-1,3,4-thiadiazol-2-yl]acetamide	1562514: Inhibition of recombinant 6His-tagged GLS1 KGA isoform (unknown origin) (63 to 669 residues) expressed in Escherichia coli using glutamine as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by amplex red staining-based horseradish peroxidase/glutamate oxidase coupled assay	ic50	0.0160	uM
3-[1-[(4-methylphenyl)methyl]triazol-4-yl]-N-[5-[(3R)-3-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]pyrrolidin-1-yl]-1,3,4-thiadiazol-2-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0166	uM
N-[5-[(3R)-3-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]pyrrolidin-1-yl]-1,3,4-thiadiazol-2-yl]-3-[1-[[4-(trifluoromethoxy)phenyl]methyl]triazol-4-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0168	uM
2-phenyl-N-[5-[[(3R)-1-pyridazin-3-ylpyrrolidin-3-yl]amino]-1,3,4-thiadiazol-2-yl]acetamide	1562514: Inhibition of recombinant 6His-tagged GLS1 KGA isoform (unknown origin) (63 to 669 residues) expressed in Escherichia coli using glutamine as substrate preincubated for 15 mins followed by substrate addition and measured after 60 mins by amplex red staining-based horseradish peroxidase/glutamate oxidase coupled assay	ic50	0.0170	uM
N-[5-[4-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]oxy]piperidin-1-yl]-1,3,4-thiadiazol-2-yl]cyclobutanecarboxamide	1601274: Inhibition of recombinant human His-tagged GAC (72 to 603 residues) expressed in Escherichia coli using glutamine as substrate incubated for 10 mins	ic50	0.0170	uM
N-[5-[4-[6-[[2-(3-heptoxyphenyl)acetyl]amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]pentanamide	2002512: Inhibition of GLS1 (unknown origin) preincubated for 10 mins followed by glutamine addition measured after 60 mins	ic50	0.0170	uM
N-[5-[4-[6-[[2-(3-octoxyphenyl)acetyl]amino]pyridazin-3-yl]butyl]-1,3,4-thiadiazol-2-yl]pentanamide	2002512: Inhibition of GLS1 (unknown origin) preincubated for 10 mins followed by glutamine addition measured after 60 mins	ic50	0.0170	uM
N-[5-[4-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]piperidin-1-yl]-1,3,4-thiadiazol-2-yl]-3-[1-[[4-(trifluoromethoxy)phenyl]methyl]triazol-4-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0171	uM
N-[6-[4-[[5-[(2-pyridin-2-ylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]piperidin-1-yl]pyridazin-3-yl]-3-[1-[[4-(trifluoromethoxy)phenyl]methyl]triazol-4-yl]propanamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0172	uM
N-[5-[4-[[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]amino]piperidin-1-yl]-1,3,4-thiadiazol-2-yl]-1-[[4-(trifluoromethyl)phenyl]methyl]pyrazole-3-carboxamide	1908385: Allosteric inhibition of human GLS1 using glutamine as substrate incubated for 60 mins by NADH/NADPH-based absorbance analysis	ic50	0.0174	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	7
Acetaminophen	increases expression, affects expression	5
Benzo(a)pyrene	increases expression	5
bisphenol A	increases expression, affects expression, decreases methylation	4
trichostatin A	affects cotreatment, increases expression, affects expression	4
diphenylarsinic acid	decreases reaction, increases degradation, decreases activity, decreases expression, affects binding	3
(+)-JQ1 compound	increases expression	3
Estradiol	increases expression, increases reaction, affects expression	3
Hydrogen Peroxide	decreases response to substance, affects expression, affects cotreatment, increases expression	3
Cyclosporine	decreases expression	3
methylmercuric chloride	decreases expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, increases expression, affects cotreatment	2
Arsenic Trioxide	increases expression, decreases response to substance	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	increases expression, affects cotreatment, increases abundance, increases oxidation	2
Arsenic	increases expression, decreases activity, increases abundance	2
Cadmium	increases expression, decreases expression, increases abundance	2
Cisplatin	increases expression, affects cotreatment, decreases expression	2
Cyclophosphamide	increases expression, affects response to substance	2
Formaldehyde	increases expression	2
Methyl Methanesulfonate	decreases expression, increases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	affects cotreatment, decreases expression, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Thapsigargin	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2

ChEMBL screening assays

187 unique, capped per target: 185 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2114738	Functional	PubChem BioAssay. qHTS for Inhibitors of Glutaminase (GLS). (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL2156343	Binding	Inhibition of glutaminase kidney isoform at 10 uM	Design, synthesis, and pharmacological evaluation of glutamate carboxypeptidase II (GCPII) inhibitors based on thioalkylbenzoic acid scaffolds. — J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8GW	Abcam HCT 116 GLS KO	Cancer cell line	Male
CVCL_B8WC	Abcam MCF-7 GLS KO	Cancer cell line	Female
CVCL_B9J5	Abcam A-549 GLS KO	Cancer cell line	Male
CVCL_SQ08	HAP1 GLS (-) 1	Cancer cell line	Male
CVCL_SQ09	HAP1 GLS (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03792360	PHASE1	WITHDRAWN	Adipose Derived SVF for Aero-digestive & Enterocutaneous Fistulae
NCT02033772	Not specified	COMPLETED	Prospective Data Collection of Patients < 6 Months of Age Undergoing Thoracoscopic Surgery
NCT02364843	Not specified	TERMINATED	A Physiological Study to Determine the Enteral Threonine Requirements in Infants Aged 1 to 6 Months
NCT03455881	Not specified	UNKNOWN	Phenotypic and Genetic Assessment of Tracheal and Esophageal Birth Defects in Patients
NCT03730454	Not specified	ACTIVE_NOT_RECRUITING	Transanastomotic Tube for Proximal Esophageal Atresia With Distal Tracheoesophageal Fistula Repair