Roles of cytochrome P450 enzymes in pharmacology and toxicology: Past, present, and future

Guengerich, F. Peter

doi:10.1016/bs.apha.2021.12.001

Cited by 17 publications

(11 citation statements)

References 157 publications

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“…Despite potent activity on SIK2 and SIK3 and encouraging selectivity against SIK1, progression of N -methylpiperazine derivative 16 was stopped owing to IC 50 shift in a CYP TDI assay in human liver microsomes. This property is undesirable because it may lead to drug–drug interaction (DDI) or idiosyncratic drug toxicity. , …”

Section: Resultsmentioning

confidence: 99%

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases

Peixoto,

Joncour,

Temal-Laib

et al. 2024

J. Med. Chem.

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The salt-inducible kinases (SIKs) SIK1, SIK2, and SIK3 belong to the adenosine monophosphate-activated protein kinase (AMPK) family of serine/threonine kinases. SIK inhibition represents a new therapeutic approach modulating pro-inflammatory and immunoregulatory pathways that holds potential for the treatment of inflammatory diseases. Here, we describe the identification of GLPG3970 (32), a first-in-class dual SIK2/SIK3 inhibitor with selectivity against SIK1 (IC 50 of 282.8 nM on SIK1, 7.8 nM on SIK2 and 3.8 nM on SIK3). We outline efforts made to increase selectivity against SIK1 and improve CYP time-dependent inhibition properties through the structure−activity relationship. The dual activity of 32 in modulating the pro-inflammatory cytokine TNFα and the immunoregulatory cytokine IL-10 is demonstrated in vitro in human primary myeloid cells and human whole blood, and in vivo in mice stimulated with lipopolysaccharide. Compound 32 shows dose-dependent activity in disease-relevant mouse pharmacological models.

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Section: Resultsmentioning

confidence: 99%

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases

Peixoto,

Joncour,

Temal-Laib

et al. 2024

J. Med. Chem.

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“…3,35,36 Under mild conditions, CYPs can facilitate stereoselective oxidation of inactive C-H bonds in organic molecules. 37,38 Studies have established a strong association between CYPs and various diseases. 36,39 Consequently, the detection of these enzymes using uorogenic agents has become a signicant area of interest.…”

Section: Chemosensors Responsive To Cytochrome P450mentioning

confidence: 99%

Real-time fluorescent monitoring of phase I xenobiotic-metabolizing enzymes

Iqbal,

Ilyas,

Akash

et al. 2024

RSC Adv.

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“…Cytochrome P450 (CYP) is a heme-containing enzyme, the terminal component of the mixed-function oxidase system, catalyzing the oxidative metabolism of endogenous substrates (e.g., steroid hormones) and xenobiotics including drugs, toxins and environmental pollutants [ 1 , 2 , 3 ]. The cytochrome P450 superfamily is grouped into families and subfamilies according to the evolution process and amino acid sequence identity [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

The Engagement of Cytochrome P450 Enzymes in Tryptophan Metabolism

et al. 2023

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Tryptophan is metabolized along three main metabolic pathways, namely the kynurenine, serotonin and indole pathways. The majority of tryptophan is transformed via the kynurenine pathway, catalyzed by tryptophan-2,3-dioxygenase or indoleamine-2,3-dioxygenase, leading to neuroprotective kynurenic acid or neurotoxic quinolinic acid. Serotonin synthesized by tryptophan hydroxylase, and aromatic L-amino acid decarboxylase enters the metabolic cycle: serotonin → N-acetylserotonin → melatonin → 5-methoxytryptamine→serotonin. Recent studies indicate that serotonin can also be synthesized by cytochrome P450 (CYP), via the CYP2D6-mediated 5-methoxytryptamine O-demethylation, while melatonin is catabolized by CYP1A2, CYP1A1 and CYP1B1 via aromatic 6-hydroxylation and by CYP2C19 and CYP1A2 via O-demethylation. In gut microbes, tryptophan is metabolized to indole and indole derivatives. Some of those metabolites act as activators or inhibitors of the aryl hydrocarbon receptor, thus regulating the expression of CYP1 family enzymes, xenobiotic metabolism and tumorigenesis. The indole formed in this way is further oxidized to indoxyl and indigoid pigments by CYP2A6, CYP2C19 and CYP2E1. The products of gut-microbial tryptophan metabolism can also inhibit the steroid-hormone-synthesizing CYP11A1. In plants, CYP79B2 and CYP79B3 were found to catalyze N-hydroxylation of tryptophan to form indole-3-acetaldoxime while CYP83B1 was reported to form indole-3-acetaldoxime N-oxide in the biosynthetic pathway of indole glucosinolates, considered to be defense compounds and intermediates in the biosynthesis of phytohormones. Thus, cytochrome P450 is engaged in the metabolism of tryptophan and its indole derivatives in humans, animals, plants and microbes, producing biologically active metabolites which exert positive or negative actions on living organisms. Some tryptophan-derived metabolites may influence cytochrome P450 expression, affecting cellular homeostasis and xenobiotic metabolism.

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Roles of cytochrome P450 enzymes in pharmacology and toxicology: Past, present, and future

Cited by 17 publications

References 157 publications

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases

Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases

Real-time fluorescent monitoring of phase I xenobiotic-metabolizing enzymes

The Engagement of Cytochrome P450 Enzymes in Tryptophan Metabolism

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