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1.
Nat Med ; 29(12): 3127-3136, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37957373

RESUMEN

Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600-1,600 mg and after 14 daily doses of ≥95% at 50-200 mg. In patients, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885 .


Asunto(s)
Dermatitis Atópica , Hidradenitis Supurativa , Humanos , Hidradenitis Supurativa/tratamiento farmacológico , Dermatitis Atópica/tratamiento farmacológico , Quinasas Asociadas a Receptores de Interleucina-1 , Resultado del Tratamiento , Piel/patología , Método Doble Ciego , Índice de Severidad de la Enfermedad
2.
J Med Chem ; 66(13): 9095-9119, 2023 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-37399505

RESUMEN

The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor (1) that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the Tsc1 gene. However, 1 showed the risk of genotoxicity in vitro. Through structure-activity relationship (SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the Tsc1 gene knockout model. Unfortunately, 9 and 11 showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.


Asunto(s)
Inhibidores mTOR , Sirolimus , Ratones , Animales , Síndrome , Sistema Nervioso Central/metabolismo , Encéfalo/metabolismo , Serina-Treonina Quinasas TOR , Adenosina Trifosfato
3.
J Med Chem ; 63(3): 1068-1083, 2020 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-31955578

RESUMEN

Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an in-house purine-based compound, optimization of the physicochemical properties of a thiazolopyrimidine series led to the discovery of the small molecule 7, a potent and selective brain-penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, 7 corrected the mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene. These results demonstrate the potential utility of this tool compound to test therapeutic hypotheses that depend on mTOR hyperactivity in the CNS.


Asunto(s)
Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Convulsiones/tratamiento farmacológico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Tiazoles/uso terapéutico , Animales , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Sitios de Unión , Encéfalo/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratas , Serina-Treonina Quinasas TOR/química , Serina-Treonina Quinasas TOR/metabolismo , Tiazoles/metabolismo , Tiazoles/farmacocinética , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética
4.
Leukemia ; 33(4): 981-994, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30185934

RESUMEN

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin-Sca-1+c-kit+CD48-CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence.


Asunto(s)
Aminoquinolinas/farmacología , Autofagia , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Neoplásicas/patología , Poliaminas/farmacología , Animales , Apoptosis , Proliferación Celular , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Ratones , Ratones Endogámicos C57BL , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Células Tumorales Cultivadas
5.
Nat Commun ; 8(1): 1804, 2017 11 27.
Artículo en Inglés | MEDLINE | ID: mdl-29180704

RESUMEN

Vps34 PI3K is thought to be the main producer of phosphatidylinositol-3-monophosphate, a lipid that controls intracellular vesicular trafficking. The organismal impact of systemic inhibition of Vps34 kinase activity is not completely understood. Here we show that heterozygous Vps34 kinase-dead mice are healthy and display a robustly enhanced insulin sensitivity and glucose tolerance, phenotypes mimicked by a selective Vps34 inhibitor in wild-type mice. The underlying mechanism of insulin sensitization is multifactorial and not through the canonical insulin/Akt pathway. Vps34 inhibition alters cellular energy metabolism, activating the AMPK pathway in liver and muscle. In liver, Vps34 inactivation mildly dampens autophagy, limiting substrate availability for mitochondrial respiration and reducing gluconeogenesis. In muscle, Vps34 inactivation triggers a metabolic switch from oxidative phosphorylation towards glycolysis and enhanced glucose uptake. Our study identifies Vps34 as a new drug target for insulin resistance in Type-2 diabetes, in which the unmet therapeutic need remains substantial.


Asunto(s)
Resistencia a la Insulina , Mitocondrias/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/fisiología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Autofagia/fisiología , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasas Clase III , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Técnicas de Sustitución del Gen , Glucosa/análisis , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Glucólisis/fisiología , Hepatocitos , Heterocigoto , Humanos , Insulina/metabolismo , Hígado/citología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Animales , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Mioblastos , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Cultivo Primario de Células
6.
ACS Med Chem Lett ; 7(1): 72-6, 2016 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-26819669

RESUMEN

Autophagy is a dynamic process that regulates lysosomal-dependent degradation of cellular components. Until recently the study of autophagy has been hampered by the lack of reliable pharmacological tools, but selective inhibitors are now available to modulate the PI 3-kinase VPS34, which is required for autophagy. Here we describe the discovery of potent and selective VPS34 inhibitors, their pharmacokinetic (PK) properties, and ability to inhibit autophagy in cellular and mouse models.

7.
Nat Cell Biol ; 16(11): 1069-79, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25327288

RESUMEN

Cells rely on autophagy to clear misfolded proteins and damaged organelles to maintain cellular homeostasis. In this study we use the new autophagy inhibitor PIK-III to screen for autophagy substrates. PIK-III is a selective inhibitor of VPS34 that binds a unique hydrophobic pocket not present in related kinases such as PI(3)Kα. PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. By performing ubiquitin-affinity proteomics on PIK-III-treated cells we identified substrates including NCOA4, which accumulates in ATG7-deficient cells and co-localizes with autolysosomes. NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion. Interestingly, Ncoa4(-/-) mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells. Taken together, the results of this study provide a new mechanism for selective autophagy of ferritin and reveal a previously unappreciated role for autophagy and NCOA4 in the control of iron homeostasis in vivo.


Asunto(s)
Autofagia/fisiología , Fosfatidilinositol 3-Quinasas Clase III/antagonistas & inhibidores , Ferritinas/metabolismo , Homeostasis/fisiología , Hierro/metabolismo , Coactivadores de Receptor Nuclear/metabolismo , Animales , Autofagia/efectos de los fármacos , Células Cultivadas , Humanos , Lisosomas/metabolismo , Ratones , Fagosomas/metabolismo , Unión Proteica
9.
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
10.
J Med Chem ; 53(19): 6867-88, 2010 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-20822181

RESUMEN

A potent class of anticancer, human farnesyltransferase (hFTase) inhibitors has been identified by "piggy-backing" on potent, antimalarial inhibitors of Plasmodium falciparum farnesyltransferase (PfFTase). On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating the extensive structure-activity relationship (SAR) study reported herein. Our most potent inhibitor is compound 1f, which exhibited an in vitro hFTase IC(50) value of 25 nM and a whole cell H-Ras processing IC(50) value of 90 nM. Moreover, it is noteworthy that several of our inhibitors proved highly selective for hFTase (up to 333-fold) over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-I). A crystal structure of inhibitor 1a co-crystallized with farnesyl pyrophosphate (FPP) in the active site of rat FTase illustrates that the para-benzonitrile moiety of 1a is stabilized by a π-π stacking interaction with the Y361ß residue, suggesting a structural explanation for the observed importance of this component of our inhibitors.


Asunto(s)
Antineoplásicos/síntesis química , Etilenodiaminas/síntesis química , Farnesiltransferasa/antagonistas & inhibidores , Modelos Moleculares , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Dominio Catalítico , Línea Celular , Cristalografía por Rayos X , Diseño de Fármacos , Etilenodiaminas/química , Etilenodiaminas/farmacología , Humanos , Estructura Molecular , Nitrilos/síntesis química , Nitrilos/química , Nitrilos/farmacología , Plasmodium falciparum/enzimología , Unión Proteica , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología
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