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Literature summary for 1.8.5.8 extracted from

  • Jackson, M.R.; Cox, K.D.; Baugh, S.D.P.; Wakeen, L.; Rashad, A.A.; Lam, P.Y.S.; Polyak, B.; Jorns, M.S.
    Discovery of a first-in-class inhibitor of sulfide quinone oxidoreductase that protects against adverse cardiac remodeling and heart failure (2022), Cardiovasc. Res., 118, 1771-1784 .
    View publication on PubMed
Search for more literature for 1.8.5.8

Application

Application Comment Organism
drug development the coenzyme Q-binding pocket in human SQOR is a druggable target, potential of SQOR inhibitors to provide a therapeutic approach for the treatment of heart failure patients with reduced ejection fraction (HFrEF) Homo sapiens
drug development the coenzyme Q-binding pocket in human SQOR is a druggable target, potential of SQOR inhibitors to provide a therapeutic approach for the treatment of heart failure patients with reduced ejection fraction (HFrEF) Mus musculus

Inhibitors

Inhibitors Comment Organism Structure
2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile HTS12441 Homo sapiens
2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile HTS12441 Mus musculus
2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile HTS12441 Rattus norvegicus
2-methoxy-4-phenyl-5H-indeno[1,2-b]pyridine-3-carbonitrile RH00520 Homo sapiens
2-methoxy-4-phenyl-5H-indeno[1,2-b]pyridine-3-carbonitrile RH00520 Mus musculus
2-methoxy-4-phenyl-5H-indeno[1,2-b]pyridine-3-carbonitrile RH00520 Rattus norvegicus
4-(2-chlorophenyl)-2-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile HTS12442 Homo sapiens
4-(2-chlorophenyl)-2-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile HTS12442 Mus musculus
4-(2-chlorophenyl)-2-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile HTS12442 Rattus norvegicus
4-(4-aminophenyl)-6-methoxy-3'-methyl[2,2'-bipyridine]-5-carbonitrile STI1, SQOR-targeted inhibitor 1, STI1 is a potent and highly selective inhibitor of SQOR. The first-in-class inhibitor of sulfide:quinone oxidoreductase binds to the CoQ-binding pocket in human SQOR and protects against adverse cardiac remodeling and heart failure. Ability of STI1 to protect against pathological remodelling of the left ventricle and the progression to heart failure patients with reduced ejection fraction (HFrEF). Docking of STI1 to ligand-free SQOR (PDB ID 6M06) and modeling of the SQOR-STI1 complex Homo sapiens
4-(4-aminophenyl)-6-methoxy-3'-methyl[2,2'-bipyridine]-5-carbonitrile STI1, SQOR-targeted inhibitor 1, STI1 is a potent and highly selective inhibitor of SQOR. The first-in-class inhibitor of sulfide:quinone oxidoreductase binds to the CoQ-binding pocket in SQOR and protects against adverse cardiac remodeling and heart failure Mus musculus
4-(4-aminophenyl)-6-methoxy-3'-methyl[2,2'-bipyridine]-5-carbonitrile STI1, SQOR-targeted inhibitor 1, STI1 is a potent and highly selective inhibitor of SQOR. STI1 is a competitive inhibitor that binds with high selectivity to the coenzyme Q-binding pocket in SQOR. STI1 exhibits very low cytotoxicity and attenuats the hypertrophic response of neonatal rat ventricular cardiomyocytes and H9c2 cells induced by neurohormonal stressors Rattus norvegicus
ethyl [(3-cyano-4,6-diphenylpyridin-2-yl)oxy]acetate HTS07545 Homo sapiens
ethyl [(3-cyano-4,6-diphenylpyridin-2-yl)oxy]acetate HTS07545 Mus musculus
ethyl [(3-cyano-4,6-diphenylpyridin-2-yl)oxy]acetate HTS07545 Rattus norvegicus
additional information inhibitor identification by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. The coenzyme Q-binding pocket in human SQOR is a druggable target. Discovery of over 500 compounds that inhibit SQOR with IC50 below 0.02 mM, and discovery of a potent series (class A/A') of SQOR inhibitors, which block substrate access to the CoQ-binding site leading to competitive inhibition Homo sapiens
additional information inhibitor identification by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. The coenzyme Q-binding pocket in human SQOR is a druggable target. Discovery of over 500 compounds that inhibit SQOR with IC50 below 0.02 mM, and discovery of a potent series (class A/A') of SQOR inhibitors, which block substrate access to the CoQ-binding site leading to competitive inhibition Mus musculus
additional information inhibitor identification by high-throughput screening of a small-molecule library, followed by focused medicinal chemistry optimization and structure-based design. STI1 is able to inhibit hypertrophic growth of neonatal rat ventricular cardiomyocytes (NRVMs) and H9c2 cells induced by various agonists, e.g. angiotensin II Rattus norvegicus

Localization

Localization Comment Organism GeneOntology No. Textmining
mitochondrion
-
 Homo sapiens 5739
-
mitochondrion
-
 Rattus norvegicus 5739
-
mitochondrion
-
 Mus musculus 5739
-

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
hydrogen sulfide + glutathione + quinone Homo sapiens
-
 S-sulfanylglutathione + quinol
-
 ir
hydrogen sulfide + glutathione + quinone Rattus norvegicus
-
 S-sulfanylglutathione + quinol
-
 ir
hydrogen sulfide + glutathione + quinone Mus musculus
-
 S-sulfanylglutathione + quinol
-
 ir

Organism

Organism UniProt Comment Textmining
Homo sapiens Q9Y6N5
-
-
Mus musculus Q9R112
-
-
Rattus norvegicus B0BMT9
-
-

Source Tissue

Source Tissue Comment Organism Textmining
aorta
-
 Homo sapiens
-
aorta
-
 Mus musculus
-
cardiac muscle fiber ventricular Rattus norvegicus
-
H9c2 cell
-
 Rattus norvegicus
-
heart
-
 Homo sapiens
-
heart
-
 Rattus norvegicus
-
heart
-
 Mus musculus
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
hydrogen sulfide + glutathione + decylubiquinone
-
 Homo sapiens S-sulfanylglutathione + decylubiquinol
-
 ir
hydrogen sulfide + glutathione + decylubiquinone
-
 Rattus norvegicus S-sulfanylglutathione + decylubiquinol
-
 ir
hydrogen sulfide + glutathione + decylubiquinone
-
 Mus musculus S-sulfanylglutathione + decylubiquinol
-
 ir
hydrogen sulfide + glutathione + quinone
-
 Homo sapiens S-sulfanylglutathione + quinol
-
 ir
hydrogen sulfide + glutathione + quinone
-
 Rattus norvegicus S-sulfanylglutathione + quinol
-
 ir
hydrogen sulfide + glutathione + quinone
-
 Mus musculus S-sulfanylglutathione + quinol
-
 ir

Synonyms

Synonyms Comment Organism
SQOR
-
 Homo sapiens
SQOR
-
 Rattus norvegicus
SQOR
-
 Mus musculus
sulfide:quinone oxidoreductase
-
 Homo sapiens
sulfide:quinone oxidoreductase
-
 Rattus norvegicus
sulfide:quinone oxidoreductase
-
 Mus musculus

Cofactor

Cofactor Comment Organism Structure
decylubiquinone
-
 Homo sapiens
decylubiquinone
-
 Rattus norvegicus
decylubiquinone
-
 Mus musculus

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.0000048
-
 2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile pH and temperature not specified in the publication Homo sapiens
0.0000115
-
 2-methoxy-4-phenyl-5H-indeno[1,2-b]pyridine-3-carbonitrile pH and temperature not specified in the publication Homo sapiens
0.0000144
-
 4-(4-aminophenyl)-6-methoxy-3'-methyl[2,2'-bipyridine]-5-carbonitrile pH and temperature not specified in the publication Homo sapiens
0.000174
-
 4-(2-chlorophenyl)-2-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile pH and temperature not specified in the publication Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0000094
-
 pH and temperature not specified in the publication Homo sapiens 2-ethoxy-4-(4-fluorophenyl)-5H-indeno[1,2-b]pyridine-3-carbonitrile
0.000021
-
 pH and temperature not specified in the publication Homo sapiens 2-methoxy-4-phenyl-5H-indeno[1,2-b]pyridine-3-carbonitrile
0.000029
-
 pH and temperature not specified in the publication Homo sapiens 4-(4-aminophenyl)-6-methoxy-3'-methyl[2,2'-bipyridine]-5-carbonitrile
0.00003
-
 pH and temperature not specified in the publication Homo sapiens ethyl [(3-cyano-4,6-diphenylpyridin-2-yl)oxy]acetate
0.00034
-
 pH and temperature not specified in the publication Homo sapiens 4-(2-chlorophenyl)-2-methoxy-5H-indeno[1,2-b]pyridine-3-carbonitrile

General Information

General Information Comment Organism
malfunction STI1 dramatically improves survival, preserves cardiac function, and prevents the progression to HFrEF by impeding the transition from compensated to decompensated left ventricle hypertrophy Homo sapiens
malfunction treatment of transverse aortic constriction (TAC) mice with enzyme SQOR inhibitor STI1 mitigates the development of cardiomegaly, pulmonary congestion, dilatation of the left ventricle, and cardiac fibrosis and decreases the pressure gradient across the aortic constriction. STI1 dramatically improves survival, preserves cardiac function, and prevents the progression to HFrEF by impeding the transition from compensated to decompensated left ventricle hypertrophy Rattus norvegicus
malfunction treatment of transverse aortic constriction (TAC) mice with enzyme SQOR inhibitor STI1 mitigates the development of cardiomegaly, pulmonary congestion, dilatation of the left ventricle, and cardiac fibrosis and decreases the pressure gradient across the aortic constriction. STI1 mitigates the pressure gradient across the aortic constriction created by TAC Mus musculus
metabolism hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Heart failure patients with reduced ejection fraction (HFrEF) exhibit low levels of H2S. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling Homo sapiens
metabolism hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling Rattus norvegicus
metabolism hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling Mus musculus
physiological function hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Heart failure patients with reduced ejection fraction (HFrEF) exhibit low levels of H2S. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling Homo sapiens
physiological function hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling Rattus norvegicus
physiological function hydrogen sulfide (H2S) is a potent signalling molecule that activates diverse cardioprotective pathways by posttranslational modification (persulfidation) of cysteine residues in upstream protein targets. Sulfide:quinone oxidoreductase (SQOR) catalyses the first irreversible step in the metabolism of H2S and plays a key role in regulating H2S-mediated signalling Mus musculus