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1.
Nat Med ; 29(1): 115-126, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36658425

RESUMO

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Neoplasias , Animais , Camundongos , Antineoplásicos/efeitos adversos , Inibidores de Histona Desacetilases/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Neoplasias/patologia , Fosforilação Oxidativa , Humanos
2.
Cancer Res ; 81(21): 5572-5581, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34518211

RESUMO

Oxidative phosphorylation (OXPHOS) is an active metabolic pathway in many cancers. RNA from pretreatment biopsies from patients with triple-negative breast cancer (TNBC) who received neoadjuvant chemotherapy demonstrated that the top canonical pathway associated with worse outcome was higher expression of OXPHOS signature. IACS-10759, a novel inhibitor of OXPHOS, stabilized growth in multiple TNBC patient-derived xenografts (PDX). On gene expression profiling, all of the sensitive models displayed a basal-like 1 TNBC subtype. Expression of mitochondrial genes was significantly higher in sensitive PDXs. An in vivo functional genomics screen to identify synthetic lethal targets in tumors treated with IACS-10759 found several potential targets, including CDK4. We validated the antitumor efficacy of the combination of palbociclib, a CDK4/6 inhibitor, and IACS-10759 in vitro and in vivo. In addition, the combination of IACS-10759 and multikinase inhibitor cabozantinib had improved antitumor efficacy. Taken together, our data suggest that OXPHOS is a metabolic vulnerability in TNBC that may be leveraged with novel therapeutics in combination regimens. SIGNIFICANCE: These findings suggest that triple-negative breast cancer is highly reliant on OXPHOS and that inhibiting OXPHOS may be a novel approach to enhance efficacy of several targeted therapies.


Assuntos
Anilidas/farmacologia , Resistencia a Medicamentos Antineoplásicos , Metaboloma , Recidiva Local de Neoplasia/tratamento farmacológico , Oxidiazóis/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Piperidinas/farmacologia , Piridinas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose , Proliferação de Células , Quimioterapia Combinada , Feminino , Perfilação da Expressão Gênica , Genômica , Humanos , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Bioorg Med Chem Lett ; 19(9): 2574-8, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19328685

RESUMO

HCV-NS3 protease is essential for viral replication and NS3 protease inhibitors have shown proof of concept in clinical trials. Novel P2-P4 macrocycle inhibitors of NS3/4A comprising a P1 C-terminal carboxylic acid have recently been disclosed. A series of analogs, in which the carboxylic residue is replaced by phosphorous acid functionalities were synthesized and found to be inhibitors of the NS3 protease. Among them the methylphosphinate analogue showed nanomolar level of enzyme inhibition and sub-micromolar potency in the replication assay.


Assuntos
Antivirais/síntese química , Química Farmacêutica/métodos , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hepatite C/tratamento farmacológico , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Fosfatos/química , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/química
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