Structural Basis of Inhibitor Selectivity in Human Indoleamine 2,3-Dioxygenase 1 and Tryptophan Dioxygenase

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold. A focused library was prepared using a 6- or 7-step synthetic procedure to allow a systematic investigation of the structure-activity relationships of the described scaffold. Chemistry-driven modifications lead us to the discovery of our best-in-class inhibitors possessing p-trifluoromethyl (23), p-cyclohexyl (32), or p-methoxycarbonyl (20, 39) substituted aniline moieties with IC50 values in the low micromolar range. In addition to hIDO1, compounds were tested for their inhibition of indoleamine 2,3-dioxygenase 2 and tryptophan dioxygenase, and found to be selective for hIDO1. Our results thus demonstrate a successful study on IDO1-selective isoxazolo[5,4-d]pyrimidin-4(5H)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators.

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Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase 1 Influenced the Age Onset of Parkinson’s Disease

10.20944/preprints202009.0470.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Nóra Török ◽

Rita Maszlag-Török ◽

Kinga Molnár ◽

Zoltán Szolnoki ◽

Ferenc Somogyvári ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Subgroup Analysis ◽

Snp Analysis ◽

Healthy Controls ◽

Nucleotide Polymorphisms ◽

Allelic Discrimination Assay ◽

Allelic Discrimination ◽

Single Nucleotide ◽

Indoleamine 2,3 Dioxygenase ◽

Tryptophan Dioxygenase

Earlier studies reported alterations of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism in Parkinson’s disease (PD). The first rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan dioxygenase were observed upregulated, resulting elevated KYN/TRP ratios in the serum and cerebrospinal fluid samples of patients with PD. An increasing number of single nucleotide polymorphisms (SNPs) have been identified in a population of PD. However, little is known if genetic variations of the IDO contribute to disturbance of the KYN metabolism in and the pathogenesis of PD. SNP analysis of IDO1 was performed by allelic discrimination assay with fluorescently labelled TaqMan probes and a subgroup analysis was conducted according to the age of PD onset. The frame shifts variant rs34155785, intronic variant rs7820268, and promotor region variant rs9657182 SNPs of 105 PD patients without comorbidity were analyzed and compared to 129 healthy controls. No significant correlation was found in three SNPs between PD patients and healthy controls. However, the subgroup analysis revealed that A alleles of rs7820268 SNP or rs9657182 SNP carriers contribute to later onset of PD than non-carriers. The study suggested that SNPs of IDO1 influenced the age onset of PD and genotyping of SNPs in certain alleles potentially serves as a risk biomarker of PD.

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CLINICAL AND TOXICOLOGICAL RELEVANCE OF CYP2C9: Drug-Drug Interactions and Pharmacogenetics

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev.pharmtox.45.120403.095821 ◽

2005 ◽

Vol 45 (1) ◽

pp. 477-494 ◽

Cited By ~ 165

Author(s):

Allan E. Rettie ◽

Jeffrey P. Jones

Keyword(s):

Oral Anticoagulants ◽

Quantitative Structure Activity Relationship ◽

Structural Basis ◽

Cytochrome P450 Enzyme ◽

Metabolic Clearance ◽

Structure Activity ◽

Oral Hypoglycemics ◽

P450 Enzyme ◽

Qsar Models ◽

Inhibitor Selectivity

CYP2C9 is a major cytochrome P450 enzyme that is involved in the metabolic clearance of a wide variety of therapeutic agents, including nonsteroidal antiinflammatories, oral anticoagulants, and oral hypoglycemics. Disruption of CYP2C9 activity by metabolic inhibition or pharmacogenetic variability underlies many of the adverse drug reactions that are associated with the enzyme. CYP2C9 is also the first human P450 to be crystallized, and the structural basis for its substrate and inhibitor selectivity is becoming increasingly clear. New, ultrapotent inhibitors of CYP2C9 have been synthesised that aid in the development of quantitative structure-activity relationship (QSAR) models to facilitate drug redesign, and extensive resequencing of the gene and studies of its regulation will undoubtedly help us understand interindividual variability in drug response and toxicity controlled by this enzyme.

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Molecular modeling provides a structural basis for PERK inhibitor selectivity towards RIPK1

RSC Advances ◽

10.1039/c9ra08047c ◽

2020 ◽

Vol 10 (1) ◽

pp. 367-375

Author(s):

Chetan Chintha ◽

Antonio Carlesso ◽

Adrienne M. Gorman ◽

Afshin Samali ◽

Leif A. Eriksson

Keyword(s):

Molecular Modeling ◽

Molecular Modelling ◽

Structural Basis ◽

Inhibitor Selectivity

Molecular modelling explains the lack of selectivity for inhibitors GSK2606414 and GSK2656157, as compared to inhibitor AMG44.

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Substrate stereo-specificity in tryptophan dioxygenase and indoleamine 2,3-dioxygenase

Proteins Structure Function and Bioinformatics ◽

10.1002/prot.22819 ◽

2010 ◽

Vol 78 (14) ◽

pp. 2961-2972 ◽

Cited By ~ 24

Author(s):

Luciana Capece ◽

Mehrnoosh Arrar ◽

Adrian E. Roitberg ◽

Syun-Ru Yeh ◽

Marcelo A. Marti ◽

...

Keyword(s):

Indoleamine 2,3 Dioxygenase ◽

Tryptophan Dioxygenase

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Structural basis for the inhibition of poly(ADP-ribose) polymerases 1 and 2 by BMN 673, a potent inhibitor derived from dihydropyridophthalazinone

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x14015088 ◽

2014 ◽

Vol 70 (9) ◽

pp. 1143-1149 ◽

Cited By ~ 25

Author(s):

Mika Aoyagi-Scharber ◽

Anna S. Gardberg ◽

Bryan K. Yip ◽

Bing Wang ◽

Yuqiao Shen ◽

...

Keyword(s):

Binding Pocket ◽

Clinical Development ◽

Structural Basis ◽

Water Molecules ◽

The Novel ◽

Breast Cancers ◽

High Potency ◽

Damage Response ◽

Site Water ◽

Inhibitor Selectivity

Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2), which are involved in DNA damage response, are targets of anticancer therapeutics. BMN 673 is a novel PARP1/2 inhibitor with substantially increased PARP-mediated tumor cytotoxicity and is now in later-stage clinical development for BRCA-deficient breast cancers. In co-crystal structures, BMN 673 is anchored to the nicotinamide-binding pocketviaan extensive network of hydrogen-bonding and π-stacking interactions, including those mediated by active-site water molecules. The novel di-branched scaffold of BMN 673 extends the binding interactions towards the outer edges of the pocket, which exhibit the least sequence homology among PARP enzymes. The crystallographic structural analyses reported here therefore not only provide critical insights into the molecular basis for the exceptionally high potency of the clinical development candidate BMN 673, but also new opportunities for increasing inhibitor selectivity.

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Single Nucleotide Polymorphisms of Indoleamine 2,3-Dioxygenase Influenced the Age Onset of Parkinson’s Disease

10.20944/preprints202010.0172.v2 ◽

2021 ◽

Author(s):

Nóra Török ◽

Rita Maszlag-Török ◽

Kinga Molnár ◽

Zoltán Szolnoki ◽

Ferenc Somogyvári ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Subgroup Analysis ◽

Snp Analysis ◽

Healthy Controls ◽

Nucleotide Polymorphisms ◽

Allelic Discrimination Assay ◽

Allelic Discrimination ◽

Single Nucleotide ◽

Indoleamine 2,3 Dioxygenase ◽

Tryptophan Dioxygenase

Aims Earlier studies reported alterations of the kynurenine (KYN) pathway of tryptophan (TRP) metabolism in Parkinson’s disease (PD). The first rate-limiting enzymes indoleamine 2,3- dioxygenase (IDO) and tryptophan dioxygenase were observed upregulated, resulting elevated KYN/TRP ratios in the serum and cerebrospinal fluid samples of patients with PD. An increasing number of single nucleotide polymorphisms (SNPs) has been identified in a population of PD. However, little is known if genetic variations of the IDO contribute to disturbance of the KYN metabolism in and the pathogenesis of PD. Main methods SNP analysis of IDO1 was performed by allelic discrimination assay with fluorescently labelled TaqMan probes and a subgroup analysis was conducted according to the age of PD onset. The frame shifts variant rs34155785, intronic variant rs7820268, and promotor region variant rs9657182 SNPs of 105 PD patients without comorbidity were analyzed and compared to 129 healthy controls. Key findings No significant correlation was found in three SNPs between PD patients and healthy controls. However, the subgroup analysis revealed that A alleles of rs7820268 SNP or rs9657182 SNP carriers contribute to later onset of PD than non-carriers. Significance The study suggested that SNPs of IDO1 influenced the age onset of PD and genotyping of SNPs in certain alleles potentially serves as a risk biomarker of PD.

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