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Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by activating a shunt pathway that generates the toxic metabolite 24(S),25-epoxycholesterol

ABSTRACT: LUM2_708738 - MM0299-probe bound protein; LUM2_708739 - MM0299 competition; LUM2_850369 - Ro-alkyne bound protein; LUM2_850370 - Ro 48-8071 competition

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Deepak Nijhawan

PROVIDER: MSV000091046 | MassIVE | Wed Jan 11 10:24:00 GMT 2023

REPOSITORIES: MassIVE

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Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production.

Nguyen Thu P TP Wang Wentian W Sternisha Alex C AC Corley Chase D CD Wang Hua-Yu Leo HL Wang Xiaoyu X Ortiz Francisco F Lim Sang-Kyun SK Abdullah Kalil G KG Parada Luis F LF Williams Noelle S NS McBrayer Samuel K SK McDonald Jeffrey G JG De Brabander Jef K JK Nijhawan Deepak D

Cell chemical biology 20230208 2

Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of MM0299, a tetracyclic dicarboximide with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a "shunt" pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to bl ...[more]

PMID: 36758549

Similar Datasets

Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by activating a shunt pathway that generates the toxic metabolite 24(S),25-epoxycholesterol

Project description:Glioblastoma (GBM) is a common and aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of a tetracyclic dicarboximide (referred to as MM0299) identified in a screen for compounds with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a “shunt” pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. In comparison to a known LSS inhibitor, MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.

2023-01-17 | GSE222971 | GEO

Hydroxyethylene isosteres of selective neuronal nitric oxide synthase inhibitors.

Project description:Nitric oxide (NO) is an important second messenger molecule for blood pressure homeostasis, as a neurotransmitter, and in the immune defense system. Excessive NO can lead to neurodegeneration and connective tissue damage. Three different isozymes of the enzyme nitric oxide synthase regulate NO production in endothelial (eNOS), neuronal (nNOS), and macrophage (iNOS) cells. Whereas creating a lower level of NO in some cells could be beneficial, it also could be detrimental to the protective effects that NO has on other cells. Therefore, it is essential that therapeutic NOS inhibitors be made that are subtype selective. Previously, we reported a series of nitroarginine-containing dipeptide amides as potent and selective nNOS inhibitors. Here we synthesize peptidomimetic hydroxyethylene isosteres of these dipeptide amides for potential increased bioavailability. None of the compounds is as potent or selective as the dipeptide amides, but they exhibit good inhibition and selectivity. When the terminal amino group was converted to a hydroxyl group, potency and selectivity greatly diminished, supporting the importance of the terminal amino group for binding.

| S-EPMC2001161 | biostudies-literature

Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by activating a shunt pathway that generates the toxic metabolite 24(S),25-epoxycholesterol

Project description:Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by activating a shunt pathway that generates the toxic metabolite 24(S),25-epoxycholesterol

| PRJNA924316 | ENA

Development of Highly Selective Pyrimidine-Based Aldosterone Synthase (CYP11B2) Inhibitors.

Project description:Excess aldosterone production and signaling are primary contributors to numerous cardiovascular disorders including primary aldosteronism and resistant hypertension. Recently, inhibition of aldosterone synthesis via the enzyme aldosterone synthase (CYP11B2) has been pursued to ameliorate the negative effects of elevated aldosterone. Herein, we report the development of aldosterone synthase inhibitors using a pyrimidine-based metal binding group leading to the highly selective CYP11B2 inhibitor 22. Superior selectivity combined with robust pharmacokinetics afforded highly selective in vivo aldosterone suppression in a monkey model of adrenal steroidogenesis, demonstrating the potential for selective aldosterone lowering in humans with pyrimidine 22.

| S-EPMC6628572 | biostudies-literature

Structure-guided design of selective inhibitors of neuronal nitric oxide synthase.

Project description:Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of L-arginine to L-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs.

| S-EPMC3632207 | biostudies-literature

Selective L-nitroargininylaminopyrrolidine and L-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors.

Project description:Selective inhibition of the localized excess production of NO by neuronal nitric oxide synthase (nNOS) has been targeted as a potential means of treating various neurological disorders. Based on observations from the X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-amino)ethylamino]pentyl}-N'-nitroguanidine (L-Arg(NO2)-L-Dbu-NH2 (1) and 4-N-(Nomega-nitro-L-argininyl)-trans-4-amino-L-proline amide (2), a series of descarboxamide analogues was designed and synthesized (3-7). The most potent compound was aminopyrrolidine analogue 3, which exhibited better potency and selectivity for nNOS than parent compound 2. In addition, 3 provided higher lipophilicity and a lower molecular weight than 2, therefore having better physicochemical properties. Nalpha-Methylated analogues (8-11) also were prepared for increased lipophilicity of the inhibitors, but they had 4- to 5-fold weaker binding affinity compared to their parent compounds.

| S-EPMC1853295 | biostudies-literature

Development of potent and selective KDM5 covalent inhibitors

Project description:Histone lysine demethylase (KDMs) are involved in the dynamic regulation of gene expression by reversible regulation of the methylation levels on lysine residues in histone tails. Among the KDMs, the jumonji (JmjC)-domain-containing KDMs (KDM2-7) are Fe(II), 2- OG (α-ketoglutarate) and molecular oxygen-dependent enzymes that employ an oxygenase mechanism to demethylate specific methylation states at various histone sites. KDMs play a critical role in several biological processes such as cell differentiation, inflammation, cancer progression and resistance. Achieving selectivity over the different families of KDMs has been a major challenge. Here we report potent and selective KDM5 covalent inhibitors designed to target a cysteine residue only present in the KDM5 sub-family. In vitro assays show that compounds are selective for the KDM5 sub-family, showing potencies in the low nanomolar range, with higher affinity for KDM5A/B. The covalent binding to the targeted proteins was proved by MS. A kinetic approach was studied in order to describe the components of overall inhibitor potency (reversible binding and chemical reactivity), showing a time-dependent decrease of IC50 values for irreversible inhibition. Additional 2-OG competition assays show that compounds were non 2-OG competitive and target engagement and ChIPs-seq assays showed that the compounds inhibited the KDM5 members in cells in the low micromolar and they induce a global increase of the H3K4Me3 mark.

2018-12-10 | GSE118589 | GEO

Potent and selective neuronal nitric oxide synthase inhibitors with improved cellular permeability.

Project description:Recently, a series of potent and selective neuronal nitric oxide synthase inhibitors containing two basic nitrogen atoms was reported (Ji, H.; Stanton, B. Z.; Igarashi, J.; Li, H.; Martásek, P.; Roman, L. J.; Poulos, T. L.; Silverman, R. B. J. Am. Chem. Soc. 2008, 130, 3900-3914). In an effort to improve their bioavailability, three compounds (2a-c) were designed with electron-withdrawing groups near one of the basic nitrogen atoms to lower its pK(a). Inhibition studies with these compounds showed that two of them not only retained most of the potency and selectivity of the best analogue of the earlier series, but also showed improved membrane permeability based on data from a cell-based assay.

| S-EPMC2818568 | biostudies-literature

Biomolecular study of human thymidylate synthase conformer-selective inhibitors: New chemotherapeutic approach.

Project description:Thymidylate synthase (TS) is a well-validated target for the therapy of adult cancers. Propane-1,3-diphosphonic acid (PDPA) has significant inhibitory properties against human thymidylate synthase (hTS) relative to mouse TS which is not predicted to adopt an inactive conformer. The current research aims to identify novel, lead inhibitors of hTS and examine the prediction that they bind selectively to hTS enzymes existing in different conformational equilibria. Conformer-selectivity was evaluated through performing activity inhibition studies, as well as intrinsic fluorescence (IF) studies in comparison to the known orthosteric inhibitor raltitrexed (RTX). Human TS was isolated from recombinant bacteria expressing either native hTS, capable of conformational switching, or an actively stabilized mutant (R163K-hTS). The examined test compounds were rationally or virtually predicted to have inhibitory activity against hTS. Among these compounds, glutarate, N-(4-carboxyphenyl) succinamic acid, and diglycolic anhydride showed higher selectivity towards native hTS as compared to R163K-hTS. The active site inhibitor RTX showed significantly higher inhibition of R163K-hTS relative to hTS. Targeting hTS via conformational selectivity represents a future approach for overcoming reported resistance towards active-state TS analogs.

| S-EPMC5851609 | biostudies-literature

Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy.

Project description:To design a new class of selective neuronal nitric oxide synthase (NOS) inhibitors, and demonstrate that administration in a rabbit model for cerebral palsy (CP) prevents hypoxia-ischemia-induced deaths and reduces the number of newborn kits exhibiting signs of CP.We used a novel computer-based drug design method called fragment hopping to identify new chemical entities, synthesized them, and conducted in vitro enzyme inhibition studies with the three isozymes of NOS and in vivo experiments to monitor cardiovascular effects on pregnant rabbit dams, NOS activity, and NO(x) (NO and NO(2)) concentration in fetal brain, and assess neurobehavioral effects on kits born to saline- and compound treated dams.The computer-based design led to the development of powerful and highly selective compounds for inhibition of neuronal NOS over the other isozymes. After maternal administration in a rabbit model of CP, these compounds were found to distribute to fetal brain, to be nontoxic, without cardiovascular effects, inhibit fetal brain NOS activity in vivo, reduce NO concentration in fetal brain, and dramatically ameliorate deaths and number of newborn kits exhibiting signs of CP.This approach may lead to new preventive strategies for CP.

| S-EPMC2658647 | biostudies-literature

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