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The delta opioid receptor (DOR) is a crucial receptor system that regulates pain, mood, anxiety, and similar mental states. DOR agonists, such as SNC80, and DOR-neutral antagonists, such as naltrindole, were developed to investigate the DOR in vivo and as potential therapeutics for pain and depression. However, few inverse agonists and non-competitive/irreversible antagonists have been developed, and none are widely available. This leaves a gap in our pharmacological toolbox and limits our ability to investigate the biology of this receptor. Thus, we designed and synthesized the novel compounds SRI-9342 as an irreversible antagonist and SRI-45128 as an inverse agonist. These compounds were then evaluated in vitro for their binding affinity by radioligand binding, their functional activity by 35S-GTPγS coupling, and their cAMP accumulation in cells expressing the human DOR. Both compounds demonstrated high binding affinity and selectivity at the DOR, and both displayed their hypothesized molecular pharmacology of irreversible antagonism (SRI-9342) or inverse agonism (SRI-45128). Together, these results demonstrate that we have successfully designed new inverse agonists and irreversible antagonists of the DOR based on a novel chemical scaffold. These new compounds will provide new tools to investigate the biology of the DOR or even new potential therapeutics.
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Analgésicos Opioides/química , Unión Competitiva , Descubrimiento de Drogas , Receptores Opioides delta/química , Analgésicos Opioides/síntesis química , Analgésicos Opioides/farmacología , Técnicas de Química Sintética , Descubrimiento de Drogas/métodos , Humanos , Ligandos , Estructura Molecular , Unión Proteica , Receptores Opioides delta/agonistas , Relación Estructura-ActividadRESUMEN
Amyotrophic lateral sclerosis (ALS) is a rare and progressive neurodegenerative disease with unknown etiology. It is caused by the degeneration of motor neurons responsible for controlling voluntary muscles. It has been reported that mutations in the superoxide dismutase (SOD) 1 gene can lead to ALS. SOD1 abnormalities have been identified in both familial, as well as sporadic ALS cases. SOD2 is a highly inducible SOD that works in conjunction with SOD1. SOD2 can be induced through activation of NF-κBs. We previously reported that the novel small molecule, SRI-22818, increases NF-κB expression and activation and SOD2 levels in vitro and has activity in vivo in the SOD1-G93A reference model of ALS. We report herein the synthesis and biological evaluation of SRI-22818 analogs.
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Esclerosis Amiotrófica Lateral/patología , Bibliotecas de Moléculas Pequeñas/química , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Relación Estructura-Actividad , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismoRESUMEN
Wnt/ß-catenin signaling is upregulated in triple-negative breast cancer (TNBC) compared to other breast cancer subtypes and normal tissues. Current Wnt/ß-catenin inhibitors, such as niclosamide, target the pathway nonspecifically and exhibit poor pharmacokinetics/pharmacodynamics in vivo. Niclosamide targets other pathways, including mTOR, STAT3 and Notch. Novel benzimidazoles have been developed to inhibit Wnt/ß-catenin signaling with greater specificity. The compounds SRI33576 and SRI35889 were discovered to produce more cytotoxicity in TNBC cell lines than in noncancerous cells. The agents also downregulated Wnt/ß-catenin signaling mediators LRP6, cyclin D1, survivin and nuclear active ß-catenin. In addition, SRI33576 did not affect mTOR, STAT3 and Notch signaling in TNBC and noncancerous cells. SRI35889 inhibited mTOR signaling less in noncancerous than in cancerous cells, while not affecting STAT3 and Notch pathways. Compounds SRI32529, SRI35357 and SRI35361 were not selectively cytotoxic against TNBC cell lines compared to MCF10A cells. While SRI32529 inhibited Wnt/ß-catenin signaling, the compound also mitigated mTOR, STAT3 and Notch signaling. SRI33576 and SRI35889 were identified as cytotoxic and selective inhibitors of Wnt/ß-catenin signaling with therapeutic potential to treat TNBC in vivo.
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Antineoplásicos/farmacología , Bencimidazoles/farmacología , Neoplasias de la Mama Triple Negativas/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Línea Celular Tumoral , Humanos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Novel allosteric modulators of the dopamine transporter (DAT) have been identified. We have shown previously that SRI-9804 [N-(diphenylmethyl)-2-phenyl-4-quinazolinamine], SRI-20040 [N-(2,2-diphenylethyl)-2-phenyl-4-quinazolinamine], and SRI-20041 [N-(3,3-diphenylpropyl)-2-phenyl-4-quinazolinamine] partially inhibit [(125)I]RTI-55 ([(125)I]3ß-(4'-iodophenyl)tropan-2ß-carboxylic acid methyl ester) binding and [(3)H]dopamine ([(3)H]DA) uptake, slow the dissociation rate of [(125)I]RTI-55 from the DAT, and allosterically modulate d-amphetamine-induced, DAT-mediated DA release. We synthesized and evaluated the activity of >500 analogs of these ligands and report here on 36 selected compounds. Using synaptosomes prepared from rat caudate, we conducted [(3)H]DA uptake inhibition assays, DAT binding assays with [(3)H]WIN35428 ([(3)H]2ß-carbomethoxy-3ß-(4-fluorophenyl)tropane), and DAT-mediated release assays with either [(3)H]MPP(+) ([(3)H]1-methyl-4-phenylpyridinium) or [(3)H]DA. We observed three groups of [(3)H]DA uptake inhibitors: 1) full-efficacy agents with a one-site fit, 2) full-efficacy agents with a two-site fit, and 3) partial-efficacy agents with a one-site fit-the focus of further studies. These agents partially inhibited DA, serotonin, and norepinephrine uptake, yet were much less potent at inhibiting [(3)H]WIN35428 binding to the DAT. For example, SRI-29574 [N-(2,2-diphenylethyl)-2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine] partially inhibited DAT uptake, with an IC50 = 2.3 ± 0.4 nM, without affecting binding to the DAT. These agents did not alter DAT-mediated release of [(3)H]MPP(+) in the absence or presence of 100 nM d-amphetamine. SRI-29574 had no significant effect on the d-amphetamine EC50 or Emax value for DAT-mediated release of [(3)H]MPP(+). These studies demonstrate the existence of potent DAT ligands that partially block [(3)H]DA uptake, without affecting DAT binding or d-amphetamine-induced [(3)H]MPP(+) release. These compounds may prove to be useful probes of biogenic amine transporter function as well as novel therapeutics.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , 1-Metil-4-fenilpiridinio/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Núcleo Caudado/efectos de los fármacos , Núcleo Caudado/metabolismo , Cocaína/análogos & derivados , Cocaína/farmacología , Dextroanfetamina/farmacología , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Ligandos , Masculino , Ratas , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismoRESUMEN
Alzheimer's disease (AD) is the leading cause of dementia and lacks highly effective treatments. Tau-based therapies hold promise. Tau reduction prevents amyloid-ß-induced dysfunction in preclinical models of AD and also prevents amyloid-ß-independent dysfunction in diverse disease models, especially those with network hyperexcitability, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau binds several SH3 domain-containing proteins implicated in AD via its central proline-rich domain. We previously used a peptide inhibitor to demonstrate that blocking Tau interactions with SH3 domain-containing proteins ameliorates amyloid-ß-induced dysfunction. Here, we identify a top hit from high-throughput screening for small molecules that inhibit Tau-FynSH3 interactions and describe its optimization with medicinal chemistry. The resulting lead compound is a potent cell-permeable Tau-SH3 interaction inhibitor that binds Tau and prevents amyloid-ß-induced dysfunction, including network hyperexcitability. These data support the potential of using small molecule Tau-SH3 interaction inhibitors as a novel therapeutic approach to AD.
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Enfermedad de Alzheimer , Proteínas tau , Humanos , Proteínas tau/metabolismo , Péptidos beta-Amiloides/toxicidad , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Ensayos Analíticos de Alto RendimientoRESUMEN
6-Oxo and 6-thio analogs of purine were prepared based on the initial activity screening of a small, diverse purine library against Mycobacterium tuberculosis (Mtb). Certain 6-oxo and 6-thio-substituted purine analogs described herein showed moderate to good inhibitory activity. N(9)-substitution apparently enhances the anti-mycobacterial activity in the purine series described herein. Several 2-amino and 2-chloro purine analogs were also synthesized that showed moderate inhibitory activity against Mtb.
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Antituberculosos/química , Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Purinas/química , Purinas/uso terapéutico , Tuberculosis/tratamiento farmacológico , Animales , Antituberculosos/farmacología , Antituberculosos/toxicidad , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Purinas/farmacología , Purinas/toxicidad , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacología , Compuestos de Sulfhidrilo/uso terapéutico , Compuestos de Sulfhidrilo/toxicidad , Células VeroRESUMEN
Lipomannan (LM) and lipoarabinomannan (LAM) are key Corynebacterineae glycoconjugates that are integral components of the mycobacterial cell wall, and are potent immunomodulators during infection. LAM is a complex heteropolysaccharide synthesized by an array of essential glycosyltransferase family C (GT-C) members, which represent potential drug targets. Herein, we have identified and characterized two open reading frames from Corynebacterium glutamicum that encode for putative GT-Cs. Deletion of NCgl2100 and NCgl2097 in C. glutamicum demonstrated their role in the biosynthesis of the branching α(1â2)-Manp residues found in LM and LAM. In addition, utilizing a chemically defined nonasaccharide acceptor, azidoethyl 6-O-benzyl-α-D-mannopyranosyl-(1â6)-[α-D-mannopyranosyl-(1â6)](7) -D-mannopyranoside, and the glycosyl donor C(50) -polyprenol-phosphate-[(14) C]-mannose with membranes prepared from different C. glutamicum mutant strains, we have shown that both NCgl2100 and NCgl2097 encode for novel α(1â2)-mannopyranosyltransferases, which we have termed MptC and MptD respectively. Complementation studies and in vitro assays also identified Rv2181 as a homologue of Cg-MptC in Mycobacterium tuberculosis. Finally, we investigated the ability of LM and LAM from C. glutamicum, and C. glutamicumΔmptC and C. glutamicumΔmptD mutants, to activate Toll-like receptor 2. Overall, our study enhances our understanding of complex lipoglycan biosynthesis in Corynebacterineae and sheds further light on the structural and functional relationship of these classes of polysaccharides.
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Proteínas Bacterianas/metabolismo , Corynebacterium glutamicum/metabolismo , Lipopolisacáridos/biosíntesis , Mananos/metabolismo , Sistema de Fosfotransferasa de Azúcar del Fosfoenolpiruvato/metabolismo , Proteínas Bacterianas/genética , Vías Biosintéticas , Corynebacterium glutamicum/química , Corynebacterium glutamicum/enzimología , Corynebacterium glutamicum/genética , Lipopolisacáridos/química , Estructura Molecular , Sistema de Fosfotransferasa de Azúcar del Fosfoenolpiruvato/genéticaRESUMEN
HIV-1 Nef is an attractive target for antiretroviral drug discovery because of its role in promoting HIV-1 infectivity, replication, and host immune system avoidance. Here, we applied a screening strategy in which recombinant HIV-1 Nef protein was coupled to activation of the Src-family tyrosine kinase Hck, which enhances the HIV-1 life cycle in macrophages. Nef stimulates recombinant Hck activity in vitro, providing a robust assay for chemical library screening. High-throughput screening of more than 730â¯000 compounds using the Nef·Hck assay identified six unique hit compounds that bound directly to recombinant Nef by surface plasmon resonance (SPR) in vitro and inhibited HIV-1 replication in primary macrophages in the 0.04 to 5 µM range without cytotoxicity. Eighty-four analogs were synthesized around an isothiazolone scaffold from this series, many of which bound to recombinant Nef and inhibited HIV-1 infectivity in the low to submicromolar range. Compounds in this series restored MHC-I to the surface of HIV-infected primary cells and disrupted a recombinant protein complex of Nef with the C-terminal tail of MHC-I and the µ1 subunit of the AP-1 endocytic trafficking protein. Nef inhibitors in this class have the potential to block HIV-1 replication in myeloid cells and trigger recognition of HIV-infected cells by the adaptive immune system in vivo.
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VIH-1 , Regulación hacia Abajo , VIH-1/metabolismo , Macrófagos/metabolismo , Replicación Viral , Familia-src Quinasas/metabolismoRESUMEN
The development of novel therapeutics that exploit alterations in the activation state of key cellular signaling pathways due to mutations in upstream regulators has generated the field of personalized medicine. These first-generation efforts have focused on actionable mutations identified by deep sequencing of large numbers of tumor samples. We propose that a second-generation opportunity exists by exploiting key downstream "nodes of control" that contribute to oncogenesis and are inappropriately activated due to loss of upstream regulation and microenvironmental influences. The RNA-binding protein HuR represents such a node. Because HuR functionality in cancer cells is dependent on HuR dimerization and its nuclear/cytoplasmic shuttling, we developed a new class of molecules targeting HuR protein dimerization. A structure-activity relationship algorithm enabled development of inhibitors of HuR multimer formation that were soluble, had micromolar activity, and penetrated the blood-brain barrier. These inhibitors were evaluated for activity validation and specificity in a robust cell-based assay of HuR dimerization. SRI-42127, a molecule that met these criteria, inhibited HuR multimer formation across primary patient-derived glioblastoma xenolines (PDGx), leading to arrest of proliferation, induction of apoptosis, and inhibition of colony formation. SRI-42127 had favorable attributes with central nervous system penetration and inhibited tumor growth in mouse models. RNA and protein analysis of SRI-42127-treated PDGx xenolines across glioblastoma molecular subtypes confirmed attenuation of targets upregulated by HuR. These results highlight how focusing on key attributes of HuR that contribute to cancer progression, namely cytoplasmic localization and multimerization, has led to the development of a novel, highly effective inhibitor. SIGNIFICANCE: These findings utilize a cell-based mechanism of action assay with a structure-activity relationship compound development pathway to discover inhibitors that target HuR dimerization, a mechanism required for cancer promotion.
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Carcinogénesis/efectos de los fármacos , Proteína 1 Similar a ELAV/química , Multimerización de Proteína/efectos de los fármacos , Algoritmos , Animales , Apoptosis/efectos de los fármacos , Barrera Hematoencefálica , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteína 1 Similar a ELAV/metabolismo , Proteína 1 Similar a ELAV/fisiología , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Humanos , Ratones , Ratones Desnudos , Medicina de Precisión , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad , Ensayo de Tumor de Célula Madre , Regulación hacia ArribaRESUMEN
A benzo[6]annulene, 4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (1a), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC90 = 1.45 µM and viral titer reduction (VTR) of 2.5 log at 10 µM with no observed cytotoxicity (CC50 = 169 µM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, and drug-like properties of 1a resulted in a novel lead compound 8q, which possessed excellent cellular antiviral activity (EC90 = 270 nM and VTR of 4.5 log at 10 µM) and improved liver microsomal stability. CHIKV resistance to an analog of 1a, compound 1c, tracked to a mutation in the nsP3 macrodomain. Further mechanism of action studies showed compounds working through inhibition of human dihydroorotate dehydrogenase in addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed in an in vivo CHIKV challenge mouse model for compound 8q as viral replication was rescued from the pyrimidine salvage pathway.
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Antivirales/farmacología , Derivados del Benceno/química , Virus Chikungunya/fisiología , Replicación Viral/efectos de los fármacos , Animales , Antivirales/química , Antivirales/farmacocinética , Antivirales/uso terapéutico , Derivados del Benceno/metabolismo , Derivados del Benceno/farmacología , Derivados del Benceno/uso terapéutico , Sitios de Unión , Línea Celular , Supervivencia Celular/efectos de los fármacos , Fiebre Chikungunya/tratamiento farmacológico , Dihidroorotato Deshidrogenasa , Modelos Animales de Enfermedad , Femenino , Semivida , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/metabolismo , Relación Estructura-ActividadRESUMEN
Disruptor of Telomeric Silencing 1-Like (DOT1L), the sole histone H3 lysine 79 (H3K79) methyltransferase, is required for leukemogenic transformation in a subset of leukemias bearing chromosomal translocations of the Mixed Lineage Leukemia (MLL) gene, as well as other cancers. Thus, DOT1L is an attractive therapeutic target and discovery of small molecule inhibitors remain of high interest. Herein, we are presenting screening results for a unique focused library of 1200 nucleoside analogs originally produced under the aegis of the NIH Pilot Scale Library Program. The complete nucleoside set was screened virtually against DOT1L, resulting in 210 putative hits. In vitro screening of the virtual hits resulted in validation of 11 compounds as DOT1L inhibitors clustered into two distinct chemical classes, adenosine-based inhibitors and a new chemotype that lacks adenosine. Based on the developed DOT1L ligand binding model, a structure-based design strategy was applied and a second-generation of non-nucleoside DOT1L inhibitors was developed. Newly synthesized compound 25 was the most potent DOT1L inhibitor in the new series with an IC50 of 1.0 µM, showing 40-fold improvement in comparison with hit 9 and exhibiting reasonable on target effects in a DOT1L dependent murine cell line. These compounds represent novel chemical probes with a unique non-nucleoside scaffold that bind and compete with the SAM binding site of DOT1L, thus providing foundation for further medicinal chemistry efforts to develop more potent compounds.
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Médula Ósea/efectos de los fármacos , Proliferación Celular , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento/métodos , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Leucemia Experimental/tratamiento farmacológico , Nucleósidos/farmacología , Triazoles/farmacología , Animales , Médula Ósea/enzimología , Simulación por Computador , Inhibidores Enzimáticos/química , Leucemia Experimental/enzimología , Ratones , Nucleósidos/química , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
An efficient, simple convergent assembly of a homolinear alpha(1-->6)-linked octamannosyl thioglycoside was obtained starting from imidazolium cation-tagged mannosyl fluoride and thiomannoside using block couplings. During chain elongation glycosylation reactions no column chromatographic purifications were used.
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Imidazoles/química , Manósidos/química , Oligosacáridos/química , Oligosacáridos/síntesis química , Glicosilación , SolucionesRESUMEN
Arabinosyltransferases (AraTs) play a critical role in mycobacterial cell wall biosynthesis and are potential drug targets for the treatment of tuberculosis, especially multi-drug resistant forms of M. tuberculosis (MTB). Herein, we report the synthesis and acceptor/inhibitory activity of Araf alpha(1-->5) Araf disaccharides possessing deoxygenation at the reducing sugar of the disaccharide. Deoxygenation at either the C-2 or C-3 position of Araf was achieved via a free radical procedure using xanthate derivatives of the hydroxyl group. The alpha(1-->5)-linked disaccharides were produced by coupling n-octyl alpha-Araf 2-/3-deoxy, 2-fluoro glycosyl acceptors with an Araf thioglycosyl donor. The target disaccharides were tested in a cell free mycobacterial AraTs assay as well as an in vitro assay against MTB H(37)Ra and M. avium complex strains.
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Arabinosa/análogos & derivados , Disacáridos/síntesis química , Mycobacterium tuberculosis/efectos de los fármacos , Pentosiltransferasa/antagonistas & inhibidores , Antibacterianos/síntesis química , Antibacterianos/farmacología , Arabinosa/química , Arabinosa/farmacología , Disacáridos/farmacología , Mycobacterium tuberculosis/enzimología , Pentosiltransferasa/metabolismo , Especificidad por SustratoRESUMEN
Under the aegis of the Pilot Scale Library Program of the NIH Roadmap Initiative, a new library of propan-1-amine containing aza acyclic nucleosides was designed and prepared, and we now report a diverse set of 157 purine, pyrimidine, and 1,2,4-triazole- N-acetamide analogues. These new nucleoside analogues were prepared in a parallel high throughput solution-phase format. A set of diverse amines was reacted with several nucleobase N-propaldehydes utilizing reductive amination with sodium triacetoxyborohydride coupling to produce a small and diverse aza acyclic nucleoside library. All reactions were performed using 24-well reaction blocks and an automatic reagent-dispensing platform under an inert atmosphere. Final targets were purified on an automated system using solid sample loading prepacked cartridges and prepacked silica gel columns. All compounds were characterized by NMR and HRMS and were analyzed for purity by HPLC prior to submission to the Molecular Libraries Small Molecule Repository (MLSMR). Initial screening through the Molecular Libraries Probe Production Centers Network (MLPCN) demonstrated diverse and interesting biological activities.
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Nucleósidos/química , Bibliotecas de Moléculas Pequeñas/química , Acetamidas/química , Aldehídos/química , Aminación , Aminas/química , Ensayos Analíticos de Alto Rendimiento/métodos , Estructura Molecular , Purinas/química , Pirimidinas/química , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
The synthesis of complex oligosaccharides has been a challenge for researchers. Herein, we describe a strategy for the synthesis of an activated oligomannan 1 that employs ionic liquid (IL) support glycosylation methodology on an IL-tagged mannosyl fluoride donor. This method is capable of rapidly producing linear alpha(1-->6) oligomannan thioglycosides in a convenient and cost-effective manner without the need of column purification after each glycosylation step.
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Mananos/síntesis química , Glicósidos/síntesis química , Glicósidos/química , Glicosilación , Mananos/química , Estructura Molecular , EstereoisomerismoRESUMEN
Synthesis of a fluorescently labelled (dansylated) linear alpha(1-->6)-linked octamannan, using glycosyl fluoride donors and thioglycosyl acceptors is described. A selective and convergent two-stage activation progression was executed to construct di-, tetra and octa-mannosyl thioglycosides in three glycosylation steps with excellent yield. Further a 5-N,N-Dimethylaminonaphthalene-1-sulfonamidoethyl (dansyl) group was coupled to 1-azidoethyl octamannosyl thioglycoside. Global deprotection of the coupled product afforded the desired dansylated homo-linear alpha(1-->6)-linked octamannan.
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Activation of Wnt/ß-catenin signaling is associated with pancreatic and colorectal cancer, among others. To-date, there are no FDA-approved small molecule Wnt/ß-catenin inhibitors and many past efforts resulted in compounds with undesirable off-target effects. We recently identified a series of benzimidazole analogs as potent inhibitors of Wnt/ß-catenin signaling. Here, we show that the lead compound SRI36160 displayed selective Wnt inhibition and potent antiproliferative activity in pancreatic and colorectal cancer cells. Moreover, SRI36160 had no effect on STAT3 and mTORC1 signaling in pancreatic and colorectal cancer cells, and was not effective in inhibiting proliferation of non-cancerous cells. Our findings suggest that this series of benzimidazole analogs presents a novel approach for the treatment of Wnt-dependent cancers such as colorectal and pancreatic cancer.
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Bencimidazoles/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Wnt/antagonistas & inhibidores , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/antagonistas & inhibidores , Proteína de la Poliposis Adenomatosa del Colon/genética , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Neoplasias Colorrectales/patología , Humanos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/fisiología , Ratones , Mutación , Neoplasias Pancreáticas/patología , Fosforilación , Proteína Wnt3A/fisiología , beta Catenina/genéticaRESUMEN
The Wnt/ß-catenin signaling pathway is critical for the initiation and progression of most colon cancers, and has emerged as one of the most promising targets for colorectal cancer chemoprevention and treatment. In this study, we have discovered a structurally related series of quinazolines as potent inhibitors of Wnt/ß-catenin signaling in colorectal cancer cells harboring mutations in CTNNB1 or APC. We showed that the quinazoline leads suppressed Wnt/ß-catenin signaling without altering the level of ß-catenin protein in colorectal cancer cells, suggesting that they act on the downstream elements of the pathway. Moreover, the quinazoline leads displayed potent anticancer activities with IC50 values between 4.9 and 17.4 µM in colorectal cancer cells. Importantly, we also found that a structurally related quinazoline lacking inhibitory effect on Wnt/ß-catenin signaling was unable to suppress colorectal cancer cell proliferation. Together, these results suggest that the quinazoline lead compounds identified in this study have therapeutic potential for the prevention and treatment of colorectal cancer.
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Antineoplásicos/farmacología , Neoplasias Colorrectales/metabolismo , Quinazolinas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración 50 InhibidoraRESUMEN
The crystal structures of two human dihydrofolate reductase (hDHFR) ternary complexes, each with bound NADPH cofactor and a lipophilic antifolate inhibitor, have been determined at atomic resolution. The potent inhibitors 6-([5-quinolylamino]methyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (SRI-9439) and (Z)-6-(2-[2,5-dimethoxyphenyl]ethen-1-yl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (SRI-9662) were developed at Southern Research Institute against Toxoplasma gondii DHFR-thymidylate synthase. The 5-deazapteridine ring of each inhibitor adopts an unusual puckered conformation that enables the formation of identical contacts in the active site. Conversely, the quinoline and dimethoxybenzene moieties exhibit distinct binding characteristics that account for the differences in inhibitory activity. In both structures, a salt-bridge is formed between Arg70 in the active site and Glu44 from a symmetry-related molecule in the crystal lattice that mimics the binding of methotrexate to DHFR.