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1.
Cell Chem Biol ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33592188

RESUMO

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity ("nuisance compounds") are routinely encountered in cellular assays, including phenotypic and high-content screening assays. Much is known regarding compound-dependent assay interferences in cell-free assays. However, despite the essential role of cellular assays in chemical biology and drug discovery, there is considerably less known about nuisance compounds in more complex cell-based assays. In our view, a major obstacle to realizing the full potential of chemical biology will not just be difficult-to-drug targets or even the sheer number of targets, but rather nuisance compounds, due to their ability to waste significant resources and erode scientific trust. In this review, we summarize our collective academic, government, and industry experiences regarding cellular nuisance compounds. We describe assay design strategies to mitigate the impact of nuisance compounds and suggest best practices to efficiently address these compounds in complex biological settings.

2.
J Med Chem ; 63(23): 14951-14978, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33201697

RESUMO

α-Methylene-γ-lactones are present in ∼3% of known natural products, and compounds comprising this motif display a range of biological activities. However, this reactive lactone limits informed structure-activity relationships for these bioactive molecules. Herein, we describe chemically tuning the electrophilicity of the α-methylene-γ-lactone by replacement with an α-methylene-γ-lactam. Guaianolide analogues having α-methylene-γ-lactams are synthesized using the allenic Pauson-Khand reaction. Substitution of the lactam nitrogen with electronically different groups affords diverse thiol reactivity. Cellular NF-κB inhibition assays for these lactams were benchmarked against parthenolide and a synthetic α-methylene-γ-lactone showing a positive correlation between thiol reactivity and bioactivity. Cytotoxicity assays show good correlation at the outer limits of thiol reactivity but less so for compounds with intermediate reactivity. A La assay to detect reactive molecules by nuclear magnetic resonance and mass spectrometry peptide sequencing assays with the La antigen protein demonstrate that lactam analogues with muted nonspecific thiol reactivities constitute a better electrophile for rational chemical probe and therapeutic molecule design.

3.
J Med Chem ; 63(21): 12137-12155, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32804502

RESUMO

This Perspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labeled health products and CBD-associated health claims lacks a rigorous scientific foundation. CBD's reputation as a cure-all puts it in the same class as other "natural" panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the "natural" label. Literature evidence associates CBD with certain semiubiquitous, broadly screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.

4.
J Med Chem ; 63(9): 4655-4684, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32118427

RESUMO

A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 µM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 µM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.


Assuntos
Antineoplásicos/farmacologia , Histona Acetiltransferases/antagonistas & inibidores , Hidrazinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Hidrazinas/síntese química , Hidrazinas/metabolismo , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
5.
ACS Comb Sci ; 22(3): 150-155, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32065745

RESUMO

The readily available natural product stevioside provides a unique diterpene core structure that can be explored for small molecule library development by diversity-oriented synthesis and functional group transformations. Validation arrays were prepared from steviol, isosteviol, and related analogues, derived from stevioside, to produce over 90 compounds. These compounds were submitted to the NIH Molecular Libraries Small Molecule Repository for screening in the Molecular Libraries Screening Center Network. Micromolar hits were identified in multiple high-throughput assays for several library members. A cheminformatics analysis of the compounds was performed that verified the expected diversity and complexity of this set of compounds. The screening results indicate that scaffolds-derived natural products can provide screening hits against multiple target proteins.

6.
Clin Cancer Res ; 26(12): 2986-2996, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32098767

RESUMO

PURPOSE: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. EXPERIMENTAL DESIGN: Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. RESULTS: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1-/- T47D breast cancer cell line. CONCLUSIONS: This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.

7.
J Med Chem ; 63(6): 2894-2914, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32105470

RESUMO

Glutathione transferase omega-1 (GSTO1-1) is an enzyme whose function supports the activation of interleukin (IL)-1ß and IL-18 that are implicated in a variety of inflammatory disease states for which small-molecule inhibitors are sought. The potent reactivity of the active-site cysteine has resulted in reported inhibitors that act by covalent labeling. In this study, structure-activity relationship (SAR) elaboration of the reported GSTO1-1 inhibitor C1-27 was undertaken. Compounds were evaluated for inhibitory activity toward purified recombinant GSTO1-1 and for indicators of target engagement in cell-based assays. As covalent inhibitors, the kinact/KI values of selected compounds were determined, as well as in vivo pharmacokinetics analysis. Cocrystal structures of key novel compounds in complex with GSTO1-1 were also solved. This study represents the first application of a biochemical assay for GSTO1-1 to determine kinact/KI values for tested inhibitors and the most extensive set of cell-based data for a GSTO1-1 inhibitor SAR series reported to date. Our research culminated in the discovery of 25, which we propose as the preferred biochemical tool to interrogate cellular responses to GSTO1-1 inhibition.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/antagonistas & inibidores , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Desenvolvimento de Medicamentos , Glutationa Transferase/química , Glutationa Transferase/metabolismo , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade
8.
FASEB J ; 34(1): 41-65, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914647

RESUMO

While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a September, 2018 transdisciplinary workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research.


Assuntos
Produtos Biológicos/farmacologia , Pesquisa Médica Translacional/normas , Animais , Avaliação Pré-Clínica de Medicamentos , Etnobotânica , Humanos
10.
Sci Adv ; 5(9): eaaw7781, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31535023

RESUMO

Facioscapulohumeral muscular dystrophy (FSHD) results from mutations causing overexpression of the transcription factor, DUX4, which interacts with the histone acetyltransferases, EP300 and CBP. We describe the activity of a new spirocyclic EP300/CBP inhibitor, iP300w, which inhibits the cytotoxicity of the DUX4 protein and reverses the overexpression of most DUX4 target genes, in engineered cell lines and FSHD myoblasts, as well as in an FSHD animal model. In evaluating the effect of iP300w on global histone H3 acetylation, we discovered that DUX4 overexpression leads to a dramatic global increase in the total amount of acetylated histone H3. This unexpected effect requires the C-terminus of DUX4, is conserved with mouse Dux, and may facilitate zygotic genome activation. This global increase in histone H3 acetylation is reversed by iP300w, highlighting the central role of EP300 and CBP in the transcriptional mechanism underlying DUX4 cytotoxicity and the translational potential of blocking this interaction.


Assuntos
Proteína p300 Associada a E1A/metabolismo , Regulação da Expressão Gênica , Histonas/metabolismo , Proteínas de Homeodomínio/metabolismo , Distrofia Muscular Facioescapuloumeral/patologia , Mioblastos/patologia , Acetilação , Animais , Morte Celular , Células Cultivadas , Modelos Animais de Doenças , Proteína p300 Associada a E1A/genética , Feminino , Histonas/genética , Proteínas de Homeodomínio/genética , Humanos , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular Facioescapuloumeral/metabolismo , Mioblastos/metabolismo , Processamento de Proteína Pós-Traducional
11.
J Med Chem ; 62(15): 7146-7159, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31256587

RESUMO

A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC50 of 1.0 µM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 (97), a highly potent inhibitor of KAT6A (IC50 = 0.008 µM). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool.


Assuntos
Benzenossulfonatos/química , Descoberta de Drogas/métodos , Histona Acetiltransferases/antagonistas & inibidores , Histona Acetiltransferases/metabolismo , Hidrazinas/química , Animais , Benzenossulfonatos/farmacologia , Células CACO-2 , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Hidrazinas/farmacologia , Camundongos , Estrutura Secundária de Proteína
12.
Sci Rep ; 9(1): 9841, 2019 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285509

RESUMO

A large number of natural products have been advocated as anticancer agents. Many of these compounds contain functional groups characterized by chemical reactivity. It is not clear whether distinct mechanisms of action can be attributed to such compounds. We used a chemical library screening approach to demonstrate that a substantial fraction (~20%) of cytotoxic synthetic compounds containing Michael acceptor groups inhibit proteasome substrate processing and induce a cellular response characteristic of proteasome inhibition. Biochemical and structural analyses showed binding to and inhibition of proteasome-associated cysteine deubiquitinases, in particular ubiquitin specific peptidase 14 (USP14). The results suggested that compounds bind to a crevice close to the USP14 active site with modest affinity, followed by covalent binding. A subset of compounds was identified where cell death induction was closely associated with proteasome inhibition and that showed significant antineoplastic activity in a zebrafish embryo model. These findings suggest that proteasome inhibition is a relatively common mode of action by cytotoxic compounds containing Michael acceptor groups and help to explain previous reports on the antineoplastic effects of natural products containing such functional groups.


Assuntos
Antineoplásicos/administração & dosagem , Inibidores de Proteassoma/administração & dosagem , Bibliotecas de Moléculas Pequenas/administração & dosagem , Ubiquitina Tiolesterase/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Domínio Catalítico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Células HeLa , Humanos , Células MCF-7 , Complexo de Endopeptidases do Proteassoma/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química , Inibidores de Proteassoma/farmacologia , Ligação Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Ubiquitina Tiolesterase/química , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
13.
J Med Chem ; 62(5): 2485-2498, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30715882

RESUMO

A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC50 (50% inhibitory concentration) of 0.008 µM, had high in vitro potency against P. falciparum lines resistant to chloroquine (W2, IC50 = 0.0047 ± 0.0011 µM) and artemisinin (MRA1240, IC50 = 0.0086 ± 0.0010 µM). Excellent ex vivo potency of 6k was shown against clinical field isolates of both P. falciparum (IC50 = 0.022-0.034 µM) and Plasmodium vivax (IC50 = 0.0093-0.031 µM) from the blood of outpatients with uncomplicated malaria. Despite 6k being cleared relatively rapidly in mice, it suppressed parasitemia in the Peters 4-day test, with a mean ED50 value (50% effective dose) of 1.47 mg kg-1 day-1 following oral administration. The disubstituted triazine dimer 6k represents a new class of orally available antimalarial compounds of considerable interest for further development.


Assuntos
Antimaláricos/farmacologia , Triazinas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Cloroquina/farmacologia , Resistência a Medicamentos , Humanos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Estrutura Molecular , Plasmodium/classificação , Plasmodium/efeitos dos fármacos , Especificidade da Espécie , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacocinética
14.
Methods Enzymol ; 610: 1-25, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30390795

RESUMO

Drug discovery is inherently very risky. The management of these risks can enable the effective use of limited human and monetary resources. A careful attention to risk management in early discovery is especially important given that what happens in the early phases of a project may dictate the course of a research program for months or years. Risk management in early discovery starts with high-level managerial concerns: careful project selection, sufficient staffing and funding, and access to the appropriate instrumentation and tools. Herein we describe the operational elements of risk management that range from the very broad to the extremely specific. These elements have as their base an embedded culture of risk management that extends down to the experiment level, and project ownership in which all researchers anticipate risk, but are not paralyzed by it. In our model, on this base of culture stand the four pillars of early discovery risk management: right libraries, right assays, right series, and right structure-activity relationships. Appropriate attention to these considerations can decrease the risks inherent in early discovery medicinal chemistry, thereby potentially increasing the return on the investment of necessarily finite resources.


Assuntos
Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Animais , Química Farmacêutica/métodos , Humanos , Projetos de Pesquisa , Gestão de Riscos , Relação Estrutura-Atividade
15.
Curr Protoc Chem Biol ; 10(1): 91-117, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-30034947

RESUMO

Nonspecific target engagement by test compounds and purported chemical probes is a significant source of assay interference and promiscuous bioactivity in high-throughput screening (HTS) and chemical biology. Most counter-screens for thiol-reactive compounds utilize mass spectrometry or fluorescence detection, and non-proteinaceous reporters like glutathione that may not always approximate the reactivity of protein side-chains. By contrast, a La assay to detect reactive molecules by nuclear magnetic resonance (ALARM NMR) is an industry-developed protein-based [1H-13C]-heteronuclear multiple quantum coherence (HMQC) NMR counter-screen to identify nonspecific protein interactions by test compounds by reporting their tendencies to modulate the human La antigen conformation. This Current Protocol is a users-guide to the production of the 13C-labeled La antigen reporter protein, the reaction of test compounds with this reporter protein, as well as the collection and analysis of characteristic NMR spectra. Combined with other assay interference counter-screens, this assay will enhance chemical biology by helping researchers better prioritize chemical matter and which will increase the number of tractable HTS screening actives and aid in the development of better chemical probes.


Assuntos
Ensaios de Triagem em Larga Escala , Sondas Moleculares/química , Ressonância Magnética Nuclear Biomolecular , Proteínas/química , Humanos , Antígenos Comuns de Leucócito , Proteínas/síntese química , Reprodutibilidade dos Testes
16.
Neurobiol Dis ; 116: 93-105, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29758256

RESUMO

Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1-S776 phosphorylation. We further examine the implications of PKA-mediated phosphorylation at ATXN1-S776 on SCA1 through genetic manipulation of the PKA catalytic subunit Cα in Pcp2-ATXN1[82Q] mice. Here we show that pharmacologic inhibition of S776 phosphorylation in transfected cells and SCA1 patient iPSC-derived neuronal cells lead to a decrease in ATXN1. In vivo, reduction of PKA-mediated ATXN1-pS776 results in enhanced degradation of ATXN1 and improved cerebellar-dependent motor performance. These results provide evidence that PKA is a biologically important kinase for ATXN1-pS776 in cerebellar Purkinje cells.


Assuntos
Ataxia/metabolismo , Ataxina-1/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Células de Purkinje/metabolismo , Serina/metabolismo , Animais , Ataxia/genética , Ataxia/patologia , Ataxina-1/genética , Proteínas Quinases Dependentes de AMP Cíclico/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Fosforilação/fisiologia , Células de Purkinje/patologia , Serina/genética
17.
Sci Rep ; 7(1): 17832, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259211

RESUMO

Glutathione transferase Omega 1 (GSTO1-1) is an atypical GST reported to play a pro-inflammatory role in response to LPS. Here we show that genetic knockout of Gsto1 alters the response of mice to three distinct inflammatory disease models. GSTO1-1 deficiency ameliorates the inflammatory response stimulated by LPS and attenuates the inflammatory impact of a high fat diet on glucose tolerance and insulin resistance. In contrast, GSTO1-1 deficient mice show a more severe inflammatory response and increased escape of bacteria from the colon into the lymphatic system in a dextran sodium sulfate mediated model of inflammatory bowel disease. These responses are similar to those of TLR4 and MyD88 deficient mice in these models and confirm that GSTO1-1 is critical for a TLR4-like pro-inflammatory response in vivo. In wild-type mice, we show that a small molecule inhibitor that covalently binds in the active site of GSTO1-1 can be used to ameliorate the inflammatory response to LPS. Our findings demonstrate the potential therapeutic utility of GSTO1-1 inhibitors in the modulation of inflammation and suggest their possible application in the treatment of a range of inflammatory conditions.


Assuntos
Proteínas de Transporte/metabolismo , Colite/metabolismo , Glutationa Transferase/metabolismo , Inflamação/metabolismo , Obesidade/metabolismo , Animais , Proteínas de Transporte/genética , Colite/tratamento farmacológico , Colite/genética , Glutationa Transferase/genética , Inflamação/tratamento farmacológico , Inflamação/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Obesidade/tratamento farmacológico , Obesidade/genética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
18.
Nat Commun ; 8(1): 1527, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-29142305

RESUMO

Many compounds with potentially reactive chemical motifs and poor physicochemical properties are published as selective modulators of biomolecules without sufficient validation and then propagated in the scientific literature as useful chemical probes. Several histone acetyltransferase (HAT) inhibitors with these liabilities are now routinely used to probe epigenetic pathways. We profile the most commonly used HAT inhibitors and confirm that the majority of them are nonselective interference compounds. Most (15 out of 23, 65%) of the inhibitors are flagged by ALARM NMR, an industry-developed counter-screen for promiscuous compounds. Biochemical counter-screens confirm that most of these compounds are either thiol-reactive or aggregators. Selectivity panels show many of these compounds modulate unrelated targets in vitro, while several also demonstrate nonspecific effects in cell assays. These data demonstrate the usefulness of performing counter-screens for bioassay promiscuity and assay interference, and raise caution about the utility of many widely used, but insufficiently validated, compounds employed in chemical biology.


Assuntos
Inibidores Enzimáticos/química , Ensaios de Triagem em Larga Escala/métodos , Histona Acetiltransferases/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Células HEK293 , Histona Acetiltransferases/antagonistas & inibidores , Humanos , Células MCF-7 , Estrutura Molecular , Compostos de Sulfidrila/química
20.
J Med Chem ; 60(5): 1620-1637, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28074653

RESUMO

Curcumin is a constituent (up to ∼5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compounds) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double-blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed.


Assuntos
Química Farmacêutica , Curcumina/farmacologia , Animais , Curcumina/química , Curcumina/farmacocinética , Humanos
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