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1.
Blood ; 115(17): 3520-30, 2010 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-20197554

RESUMEN

Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC(50) values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)-cell growth, increases IFN-gamma production, and reduces conversion to regulatory T (T(reg))-like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86(high) DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.


Asunto(s)
Células Dendríticas/inmunología , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Neoplasias/inmunología , Linfocitos T/inmunología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Antígeno B7-2/inmunología , Antígeno B7-2/metabolismo , Técnicas de Cocultivo , Células Dendríticas/enzimología , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Linfocitos T/enzimología , Triptófano Oxigenasa/inmunología , Triptófano Oxigenasa/metabolismo
2.
ACS Med Chem Lett ; 8(5): 486-491, 2017 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-28523098

RESUMEN

A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.

3.
Cancer Res ; 62(17): 4909-15, 2002 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-12208740

RESUMEN

The thymidylate synthase reaction remains an important target for widely used anticancer agents; however, the clinical utility of these drugs is limited by the occurrence of cellular resistance. Despite the considerable amount of information available regarding mechanisms of drug action, the relative significance of downstream events that result in lethality remains unclear. In this study, we have developed a model system using the budding yeast Saccharomyces cerevisiae to dissect the influence of dUMP misincorporation into DNA as a contributing mechanism of cytotoxicity induced by antifolate agents. The activities of dUTPase and uracil-DNA glycosylase, key enzymes in uracil-DNA metabolism, were diminished or augmented, and the manipulated strains were analyzed for biochemical endpoints of toxicity. Cells overexpressing dUTPase were protected from cytotoxicity by their ability to prevent dUTP pool expansion and were able to recover from an early S-phase checkpoint arrest. In contrast, depletion of dUTPase activity leads to the accumulation of dUTP pools and enhanced sensitivity to antifolates. These cells were also arrested in early S-phase and were unable to complete DNA replication after drug withdrawal, resulting in lethality. Inactivation of uracil base excision repair induced partial resistance to early cytotoxicity (within 10 h); however, lethality ultimately resulted at later time points (12-24 h), presumably because of the detrimental effects of stable uracil misincorporation. Although these cells were able to complete replication with uracil-substituted DNA, they arrested at the G(2)-M phase. This finding may represent a novel mechanism by which the G(2)-M checkpoint is signaled by the presence of uracil-substituted DNA. Together these data provide both genetic and biochemical evidence demonstrating that lethality from antifolates in yeast is primarily dependent on uracil misincorporation into DNA, and that uracil-independent mechanisms associated with dTTP depletion play a minor role. Our findings indicate that the relative expression levels of both dUTPase and uracil-DNA glycosylase can have great influence over the efficacy of thymidylate synthase-directed chemotherapy, thereby enhancing the candidacy of these proteins as prognostic markers and alternative targets for therapeutic development.


Asunto(s)
ADN Glicosilasas , Antagonistas del Ácido Fólico/toxicidad , N-Glicosil Hidrolasas/metabolismo , Pirofosfatasas/metabolismo , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/enzimología , Daño del ADN , Reparación del ADN , Replicación del ADN/efectos de los fármacos , ADN de Hongos/biosíntesis , ADN de Hongos/efectos de los fármacos , ADN de Hongos/metabolismo , Farmacorresistencia Fúngica , N-Glicosil Hidrolasas/biosíntesis , N-Glicosil Hidrolasas/genética , Pirofosfatasas/biosíntesis , Pirofosfatasas/genética , Saccharomyces cerevisiae/genética , Uracilo/metabolismo , Uracil-ADN Glicosidasa
4.
J Med Chem ; 48(18): 5644-7, 2005 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-16134930

RESUMEN

Inhibitors of human methionine aminopeptidase type 2 (hMetAP2) are of interest as potential treatments for cancer. A new class of small molecule reversible inhibitors of hMetAP2 was discovered and optimized, the 4-aryl-1,2,3-triazoles. Compound 24, a potent inhibitor of cobalt-activated hMetAP2, also inhibits human and mouse endothelial cell growth. Using a mouse matrigel model, this reversible hMetAP2 inhibitor was also shown to inhibit angiogenesis in vivo.


Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Inhibidores de la Angiogénesis/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Triazoles/síntesis química , Aminopeptidasas/química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Sitios de Unión , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cobalto/metabolismo , Colágeno , Cristalografía por Rayos X , Combinación de Medicamentos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Endotelio Vascular/citología , Activación Enzimática , Humanos , Laminina , Metaloendopeptidasas/química , Ratones , Modelos Moleculares , Estructura Molecular , Proteoglicanos , Ratas , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología
5.
Mol Cancer Ther ; 9(2): 489-98, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20124451

RESUMEN

Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose- and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell-derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients.


Asunto(s)
Amidinas/farmacología , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Neoplasias/metabolismo , Triptófano/metabolismo , Animales , Línea Celular Tumoral , Perros , Femenino , Humanos , Sistema Inmunológico , Inmunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Quinurenina/farmacología , Ganglios Linfáticos/patología , Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Neoplasias/tratamiento farmacológico , Neoplasias/patología
6.
J Med Chem ; 52(23): 7364-7, 2009 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-19507862

RESUMEN

A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indoleamine 2,3-dioxygenase (IDO). Optimization led to the identification of 5l, which is a potent (HeLa IC(50) = 19 nM) competitive inhibitor of IDO. Testing of 5l in mice demonstrated pharmacodynamic inhibition of IDO, as measured by decreased kynurenine levels (>50%) in plasma and dose dependent efficacy in mice bearing GM-CSF-secreting B16 melanoma tumors.


Asunto(s)
Unión Competitiva , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Melanoma/enzimología , Amidinas/química , Amidinas/metabolismo , Amidinas/farmacología , Amidinas/uso terapéutico , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Concentración 50 Inhibidora , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Ratones , Modelos Moleculares , Conformación Molecular
7.
J Rheumatol ; 29(2): 230-9, 2002 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11838839

RESUMEN

OBJECTIVE: Angiopoietin- I (Ang-1) and Ang-2 are ligands for the receptor tyrosine kinase, Tie-2. Ang-1, a Tie-2 agonist, may have a vascular stabilizing role in angiogenesis, while Ang-2, an endogenous antagonist of Tie-2, may have an early role in angiogenesis, destabilizing existing vasculature. We show that these ligands are expressed by rheumatoid synovial fibroblasts (RSF) and investigate whether their expression was modulated by proinflammatory cytokines present in the joint in rheumatoid arthritis (RA). METHODS: Using quantitative PCR we determined the level of expression of these 2 ligands in RSF and chronic inflamed synovial tissue. The level of expression of these ligands after treatment with proinflammatory cytokines and hypoxia was also determined. RESULTS: We observed constitutive expression of Ang-1 and Ang-2 in RSF and chronic inflamed synovial tissue. Ang-1 was the most highly expressed ligand in late stage RA synovial fibroblasts; however, in chronic inflamed synovial tissue, Ang-2 was predominant and was expressed at strikingly high levels (70 to 120-fold increase). We observed that tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), but not interleukin 1beta or hypoxia, stimulated Ang-1 gene expression in RSE This was confirmed at the protein level as media from TNF-alpha treated RSF resulted in increased autophosphorylation of Tie-2. In contrast, TNF-alpha and TGF-beta had no effect on Ang-2 expression in RSF, but augmented expression of Ang-2 in normal synovial fibroblasts. CONCLUSION: The angiopoietins are important angiogenic factors constitutively present in RA, and their expression is modulated by certain cytokines. Ang-2 may have an important role in rheumatoid tissue where vigorous angiogenesis is occurring.


Asunto(s)
Artritis Reumatoide/metabolismo , Citocinas/fisiología , Fibroblastos/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas/metabolismo , Membrana Sinovial/metabolismo , Angiopoyetina 1 , Angiopoyetina 2 , Células Cultivadas , Medios de Cultivo Condicionados/farmacología , Citocinas/farmacología , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Fibroblastos/efectos de los fármacos , Expresión Génica , Humanos , Ligandos , Glicoproteínas de Membrana/genética , Reacción en Cadena de la Polimerasa , Proteínas/genética , ARN Mensajero/biosíntesis , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptor TIE-2 , Membrana Sinovial/efectos de los fármacos , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta/fisiología , Factor de Necrosis Tumoral alfa/farmacología , Factor de Necrosis Tumoral alfa/fisiología
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