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1.
Nat Chem Biol ; 15(2): 179-188, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30643281

RESUMEN

The identification of activating mutations in NOTCH1 in 50% of T cell acute lymphoblastic leukemia has generated interest in elucidating how these mutations contribute to oncogenic transformation and in targeting the pathway. A phenotypic screen identified compounds that interfere with trafficking of Notch and induce apoptosis via an endoplasmic reticulum (ER) stress mechanism. Target identification approaches revealed a role for SLC39A7 (ZIP7), a zinc transport family member, in governing Notch trafficking and signaling. Generation and sequencing of a compound-resistant cell line identified a V430E mutation in ZIP7 that confers transferable resistance to the compound NVS-ZP7-4. NVS-ZP7-4 altered zinc in the ER, and an analog of the compound photoaffinity labeled ZIP7 in cells, suggesting a direct interaction between the compound and ZIP7. NVS-ZP7-4 is the first reported chemical tool to probe the impact of modulating ER zinc levels and investigate ZIP7 as a novel druggable node in the Notch pathway.


Asunto(s)
Proteínas de Transporte de Catión/genética , Estrés del Retículo Endoplásmico/fisiología , Receptor Notch1/genética , Animales , Apoptosis , Proteínas Portadoras/metabolismo , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/fisiología , Línea Celular , Transformación Celular Neoplásica , Retículo Endoplásmico/fisiología , Humanos , Mutación , Transporte de Proteínas , Receptor Notch1/fisiología , Transducción de Señal , Zinc/metabolismo
2.
Proc Natl Acad Sci U S A ; 108(17): 6739-44, 2011 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-21502533

RESUMEN

The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.


Asunto(s)
Antivirales , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/metabolismo , Virus Sincitiales Respiratorios/metabolismo , Animales , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Linfocitos B/metabolismo , Linfocitos B/patología , Linfocitos B/virología , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Perros , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Células Jurkat , Infecciones por Virus Sincitial Respiratorio/patología , Linfocitos T/metabolismo , Linfocitos T/patología , Linfocitos T/virología , Células Vero
3.
ACS Med Chem Lett ; 12(8): 1288-1294, 2021 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-34413958

RESUMEN

Determination of target engagement for candidate drug molecules in the native cellular environment is a significant challenge for drug discovery programs. The cellular thermal shift assay (CETSA) has emerged as a powerful tool for determining compound target engagement through measurement of changes to a protein's thermal stability upon ligand binding. Here, we present a HiBiT thermal shift assay (BiTSA) that deploys a quantitative peptide tag for determination of compound target engagement in the native cellular environment using a high throughput, plate-based luminescence readout. We demonstrate that BiTSA can rapidly assess cellular target engagement of small molecule ligands against their cognate targets and highlight two applications of BiTSA for differentiating small molecules targeting mutant KRAS and TP53.

4.
Cell Chem Biol ; 28(9): 1271-1282.e12, 2021 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-33894161

RESUMEN

Acute kidney injury (AKI) is a life-threatening disease with no known curative or preventive therapies. Data from multiple animal models and human studies have linked dysregulation of bone morphogenetic protein (BMP) signaling to AKI. Small molecules that potentiate endogenous BMP signaling should have a beneficial effect in AKI. We performed a high-throughput phenotypic screen and identified a series of FK506 analogs that act as potent BMP potentiators by sequestering FKBP12 from BMP type I receptors. We further showed that calcineurin inhibition was not required for this activity. We identified a calcineurin-sparing FK506 analog oxtFK through late-stage functionalization and structure-guided design. OxtFK demonstrated an improved safety profile in vivo relative to FK506. OxtFK stimulated BMP signaling in vitro and in vivo and protected the kidneys in an AKI mouse model, making it a promising candidate for future development as a first-in-class therapeutic for diseases with dysregulated BMP signaling.


Asunto(s)
Lesión Renal Aguda/tratamiento farmacológico , Proteínas Morfogenéticas Óseas/metabolismo , Tacrolimus/farmacología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Ensayos Analíticos de Alto Rendimiento , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Fenotipo , Tacrolimus/análogos & derivados , Tacrolimus/química
5.
Cell Chem Biol ; 27(9): 1124-1129, 2020 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-32707038

RESUMEN

Chemogenetic libraries, collections of well-defined chemical probes, provide tremendous value to biomedical research but require substantial effort to ensure diversity as well as quality of the contents. We have assembled a chemogenetic library by data mining and crowdsourcing institutional expertise. We are sharing our approach, lessons learned, and disclosing our current collection of 4,185 compounds with their primary annotated gene targets (https://github.com/Novartis/MoaBox). This physical collection is regularly updated and used broadly both within Novartis and in collaboration with external partners.


Asunto(s)
Sondas Moleculares/química , Bibliotecas de Moléculas Pequeñas/química , Bioensayo , Bases de Datos de Compuestos Químicos , Descubrimiento de Drogas , Humanos , Aprendizaje Automático , Sondas Moleculares/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo
6.
Org Lett ; 7(12): 2449-51, 2005 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-15932220

RESUMEN

[reaction: see text] The first syntheses of the pyridazinoindazolium alkaloids nigellicine and nigeglanine hydrobromide via a common intermediate are described. Ortho-lithiation/acylation and the direct amination of an isatin ring system are the key steps in the synthesis.


Asunto(s)
Alcaloides/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Indazoles/síntesis química , Estructura Molecular , Nigella/química
7.
PLoS One ; 10(6): e0127498, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26098886

RESUMEN

Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that englerin A is a TRPC4 agonist. Both the englerin A induced current and the englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that englerin A may bind a common feature of TRP ion channels. In vivo experiments show that englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that englerin A itself is probably unsuitable for further drug development. However, since englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Sesquiterpenos de Guayano/farmacología , Canales Catiónicos TRPC/agonistas , Animales , Antineoplásicos/farmacología , Carcinoma de Células Renales/tratamiento farmacológico , Línea Celular Tumoral , Células HEK293 , Humanos , Indoles/farmacología , Neoplasias Renales/tratamiento farmacológico , Ratones , Ratones Desnudos , Piperidinas/farmacología , Interferencia de ARN , ARN Interferente Pequeño , Ratas , Canales Catiónicos TRPC/antagonistas & inhibidores , Canales Catiónicos TRPC/genética , Transfección
8.
J Med Chem ; 55(5): 2376-87, 2012 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-22315981

RESUMEN

Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.


Asunto(s)
Antibacterianos/síntesis química , Clostridioides difficile/efectos de los fármacos , Enterocolitis Seudomembranosa/tratamiento farmacológico , Tiazoles/síntesis química , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Cricetinae , Cristalografía por Rayos X , Enterococcus/efectos de los fármacos , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/química , Femenino , Masculino , Mesocricetus , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Factor Tu de Elongación Peptídica/antagonistas & inhibidores , Factor Tu de Elongación Peptídica/química , Ratas , Ratas Sprague-Dawley , Solubilidad , Staphylococcus aureus/efectos de los fármacos , Streptococcus pyogenes/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/farmacocinética , Agua
9.
J Med Chem ; 54(23): 8099-109, 2011 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-21999529

RESUMEN

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.


Asunto(s)
Antibacterianos/síntesis química , Ácidos Carboxílicos/síntesis química , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Péptidos Cíclicos/síntesis química , Tiazoles/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Área Bajo la Curva , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Cristalografía por Rayos X , Farmacorresistencia Bacteriana , Femenino , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/genética , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Mutación , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Ratas , Ratas Sprague-Dawley , Sepsis/tratamiento farmacológico , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología
10.
J Am Chem Soc ; 129(2): 376-86, 2007 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-17212418

RESUMEN

Building on prototype 1, which achieves 120 degrees of phosgene-powered unidirectional rotation to rotamer 6 (see Figure 5 in the full article), 7 was designed to accomplish repeated unidirectional rotation (see Scheme 7). Compound 7 contains an amino group on each blade of the triptycene and a 4-(dimethylamino)pyridine (DMAP) unit to selectively deliver phosgene (or its equivalent) to the amine in the "firing position". The synthesis of 7 is described: the key constructive steps are a benzyne addition to an anthracene to generate the triptycene, a stilbene photocyclization to construct the helicene, and a Stille coupling to incorporate the DMAP unit. The DMAP unit was shown to regioselectively relay 1,1'-carbonyldiimidazole (but not phosgene) to the proximal amino group, as designed, but rotation of the triptycene does not occur. Extensive attempts to troubleshoot the problem led to the conclusion that the requisite intramolecular urethane formation, as demonstrated in the prototype (1 --> 4), does not occur with 7 (to give 85) or 97 (to give 100). We speculate that either (i) hydrogen bonding between the hydroxypropyl group and functionality present in 7 but absent from 1 or (ii) a Bürgi-Dunitz (or similar) interaction involving the DMAP (see 106) prevents achievement of a conformation conducive to intramolecular urethane formation.


Asunto(s)
4-Aminopiridina/análogos & derivados , Sustancias Macromoleculares/síntesis química , Fosgeno/química , 4-Aminopiridina/química , Enlace de Hidrógeno , Sustancias Macromoleculares/química , Modelos Moleculares , Estructura Molecular , Rotación , Estereoisomerismo , Uretano/síntesis química , Uretano/química
11.
Bioorg Med Chem ; 14(1): 247-62, 2006 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-16165365

RESUMEN

Two new series of cannabinoids were prepared and their affinities for the CB1 and CB2 receptors were determined. These series are the (2'R)- and (2'S)-1-methoxy- and 1-deoxy-3-(2'-methylalkyl)-delta8-tetrahydrocannabinols, with alkyl side chains of three to seven carbon atoms. These compounds were prepared by a route that employed the enantioselective synthesis of the resorcinol precursors to the cannabinoid ring system. All of these compounds have greater affinity for the CB2 receptor than the CB1 receptor and four of them, (2'R)-1-methoxy-3-(2'-methylbutyl)-delta8-THC (JWH-359), (2'S)-1-deoxy-3-(2'-methylbutyl)-delta8-THC (JWH-352), (2'S)-1-deoxy-3-(2'-methylpentyl)-delta8-THC (JWH-255), and (2'R)-1-deoxy-3-(2'-methylpentyl)-delta8-THC (JWH-255), have good affinity (K(i) = 13-47 nM) for the CB2 receptor and little affinity (K(i) = 1493 to >10,000 nM) for the CB1 receptor. In the 1-deoxy-3-(2'-methylalkyl)-delta8-THC series, the 2'S-methyl compounds in general have greater affinity for the CB2 receptor than the corresponding 2'R isomers.


Asunto(s)
Dronabinol/síntesis química , Dronabinol/farmacología , Receptor Cannabinoide CB2/efectos de los fármacos , Ligandos , Espectroscopía de Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray , Estereoisomerismo
12.
J Org Chem ; 67(2): 457-64, 2002 Jan 25.
Artículo en Inglés | MEDLINE | ID: mdl-11798318

RESUMEN

The intermediate anion derived from the vicarious nucleophilic substitution (VNS) of hydrogen reacts with a series of alkyl halides to generate the corresponding alpha-alkylated conventional VNS product in a one-pot process. This one-pot VNS-alkylation reaction offers a convenient route to a range alpha-substituted nitrobenzyl phosphine oxides, sulfones, and esters via a three-component coupling reaction. Reactions of alpha-chloroethyl phenyl sulfone (14) and ethyl 2-chloropropionate (16) with nitrobenzene followed by subsequent addition of an alkylating agent give a series of sulfones and esters bearing an alpha-aryl quaternary center. The VNS-alkylation protocol has been applied to the synthesis of derivatives of Indoprofen from nitrobenzene using readily available inexpensive starting materials. Indoprofen itself was prepared using the conventional VNS reaction in four steps and 24% overall yield from nitrobenzene.


Asunto(s)
Indoprofeno , Nitrobencenos/química , Nitrobencenos/síntesis química , Propionatos/síntesis química , Alquilación , Catálisis , Química Orgánica/métodos , Cromatografía en Capa Delgada , Ésteres/química , Indoprofeno/análogos & derivados , Indoprofeno/síntesis química , Indoprofeno/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Propionatos/química , Sulfonas/química
13.
Bioorg Med Chem ; 10(12): 4119-29, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12413866

RESUMEN

Three series of new cannabinoids were prepared and their affinities for the CB(1) and CB(2) cannabinoid recptors were determined. These are the 1-methoxy-3-(1',1'-dimethylalkyl)-, 1-deoxy-11-hydroxy-3-(1',1'-dimethylalkyl)- and 11-hydroxy-1-methoxy-3-(1',1'-dimethylalkyl)-Delta(8)-tetrahydrocannabinols, which contain alkyl chains from dimethylethyl to dimethylheptyl appended to C-3 of the cannabinoid. All of these compounds have greater affinity for the CB(2) receptor than for the CB(1) receptor, however only 1-methoxy-3-(1',1'-dimethylhexyl)-Delta(8)-THC (JWH-229, 6e) has effectively no affinity for the CB(1) receptor (K(i)=3134+/-110nM) and high affinity for CB(2) (K(i)=18+/-2nM).


Asunto(s)
Dronabinol/síntesis química , Dronabinol/farmacología , Receptores de Droga/química , Animales , Química Encefálica , Línea Celular , Dronabinol/química , Humanos , Ligandos , Ratones , Ensayo de Unión Radioligante , Receptores de Cannabinoides , Relación Estructura-Actividad
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