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1.
J Med Chem ; 66(8): 5907-5936, 2023 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-37017629

RESUMEN

CCT251236 1, a potent chemical probe, was previously developed from a cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, a transcription factor that supports malignancy. Owing to its activity against models of refractory human ovarian cancer, 1 was progressed into lead optimization. The reduction of P-glycoprotein efflux became a focus of early compound optimization; central ring halogen substitution was demonstrated by matched molecular pair analysis to be an effective strategy to mitigate this liability. Further multiparameter optimization led to the design of the clinical candidate, CCT361814/NXP800 22, a potent and orally bioavailable fluorobisamide, which caused tumor regression in a human ovarian adenocarcinoma xenograft model with on-pathway biomarker modulation and a clean in vitro safety profile. Following its favorable dose prediction to human, 22 has now progressed to phase 1 clinical trial as a potential future treatment for refractory ovarian cancer and other malignancies.


Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Factores de Transcripción/metabolismo , Neoplasias Ováricas/patología , Línea Celular Tumoral , Antineoplásicos/farmacología
2.
J Med Chem ; 60(1): 180-201, 2017 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-28004573

RESUMEN

Phenotypic screens, which focus on measuring and quantifying discrete cellular changes rather than affinity for individual recombinant proteins, have recently attracted renewed interest as an efficient strategy for drug discovery. In this article, we describe the discovery of a new chemical probe, bisamide (CCT251236), identified using an unbiased phenotypic screen to detect inhibitors of the HSF1 stress pathway. The chemical probe is orally bioavailable and displays efficacy in a human ovarian carcinoma xenograft model. By developing cell-based SAR and using chemical proteomics, we identified pirin as a high affinity molecular target, which was confirmed by SPR and crystallography.


Asunto(s)
Amidas/química , Proteínas Portadoras/química , Proteínas de Unión al ADN/química , Proteínas Nucleares/química , Quinolinas/química , Factores de Transcripción/química , Administración Oral , Amidas/administración & dosificación , Amidas/farmacología , Disponibilidad Biológica , Espectroscopía de Resonancia Magnética con Carbono-13 , Dioxigenasas , Descubrimiento de Drogas , Factores de Transcripción del Choque Térmico , Ligandos , Espectroscopía de Protones por Resonancia Magnética , Quinolinas/administración & dosificación , Quinolinas/farmacología , Espectrometría de Masa por Ionización de Electrospray
3.
Mol Pharmacol ; 89(5): 593-605, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26916831

RESUMEN

Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. [(3)H]-QAW039 displayed high affinity for the human CRTh2 receptor (1.14 ± 0.44 nM) expressed in Chinese hamster ovary cells, the binding being reversible and competitive with the native agonist prostaglandin D2(PGD2). The binding kinetics of QAW039 determined directly using [(3)H]-QAW039 revealed mean kinetic on (kon) and off (koff) values for QAW039 of 4.5 × 10(7)M(-1)min(-1)and 0.048 minute(-1), respectively. Importantly, thekoffof QAW039 (half-life = 14.4 minutes) was >7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD2-stimulated [(35)S]-GTPγS activation, and its effects were not fully reversed by increasing concentrations of PGD2after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor. In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for >180 minutes. All CRTh2 antagonists tested inhibited PGD2-stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD2-induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD2concentrations, which may be clinically relevant.


Asunto(s)
Antialérgicos/farmacología , Drogas en Investigación/farmacología , Ácidos Indolacéticos/farmacología , Piridinas/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Células Th2/efectos de los fármacos , Acetatos/química , Acetatos/metabolismo , Acetatos/farmacología , Animales , Antialérgicos/química , Antialérgicos/metabolismo , Unión Competitiva , Células CHO , Forma de la Célula/efectos de los fármacos , Células Cultivadas , Cricetulus , Drogas en Investigación/química , Drogas en Investigación/metabolismo , Eosinófilos/citología , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Eosinófilos/metabolismo , Humanos , Ácidos Indolacéticos/química , Ácidos Indolacéticos/metabolismo , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Cinética , Ligandos , Prostaglandina D2/antagonistas & inhibidores , Prostaglandina D2/metabolismo , Piridinas/química , Piridinas/metabolismo , Receptores Inmunológicos/agonistas , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/agonistas , Receptores de Prostaglandina/genética , Receptores de Prostaglandina/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Solubilidad , Células Th2/citología , Células Th2/inmunología , Células Th2/metabolismo , Tritio
4.
J Pharm Biomed Anal ; 52(1): 86-92, 2010 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-20047815

RESUMEN

This paper describes the application of fully automated on-line solid phase extraction to the bioanalysis of three example compounds using the Symbiosis platform. The on-line assay performance is compared to off-line methodologies for the same compounds. The three example compounds possess a variety of physicochemical properties and different extraction modes were applied in off-line methods. These methods were developed through optimisation of solid phase or liquid-liquid extraction and chromatographic separation conditions for each of the analytes. Both on-line and off-line methods were evaluated for linearity, carryover, imprecision and inaccuracy. Experiments were also performed investigating modification of ionisation and selectivity against different batches of plasma. On-line and off-line methods were found to be comparable in performance. In conclusion, on-line methodology has distinct advantages for the analysis of large numbers of samples with a marked reduction in manual operation.


Asunto(s)
Automatización de Laboratorios , Sistemas en Línea , Extracción en Fase Sólida , Tecnología Farmacéutica/métodos , Cromatografía de Fase Inversa , Fluconazol/sangre , Humanos , Indanos/sangre , Espectrometría de Masas , Propionatos/sangre , Reproducibilidad de los Resultados , Temperatura
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