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1.
J Med Chem ; 67(2): 1500-1512, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38227216

RESUMO

Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC50 value of 30 nM and induces IL-2 production in T-cells with an EC50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.


Assuntos
Proteínas Proto-Oncogênicas c-cbl , Ubiquitina-Proteína Ligases , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Linfócitos T/metabolismo , Fosforilação , Ubiquitina/metabolismo
2.
Bioorg Med Chem Lett ; 23(4): 979-84, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23317569

RESUMO

This Letter describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent exploration of structure-activity relationships and optimization of drug metabolism and pharmacokinetic properties led to the identification of potent, selective and orally bioavailable ACK1 inhibitors.


Assuntos
Imidazóis/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazinas/química , Administração Oral , Animais , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/farmacocinética , Pirazinas/farmacologia , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 23(15): 4381-7, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23773865
4.
ACS Med Chem Lett ; 14(12): 1848-1856, 2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38116444

RESUMO

Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that is responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity justified our discovery effort toward Cbl-b inhibitors that might show therapeutic promise in immuno-oncology, where activation of the immune system can drive the recognition and killing of cancer cells. We undertook a high-throughput screening campaign followed by structure-enabled optimization to develop a novel benzodiazepine series of potent Cbl-b inhibitors. This series displayed nanomolar levels of biochemical potency, as well as potent T-cell activation. The functional activity of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based cellular assays.

5.
Bioorg Med Chem Lett ; 21(4): 1176-80, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21251824

RESUMO

Preclinical and emerging clinical evidence suggests that inhibiting insulin-like growth factor 1 receptor (IGF-1R) signaling may offer a promising therapeutic strategy for the treatment of several types of cancer. This Letter describes the medicinal chemistry effort towards a series of 8-amino-imidazo[1,5-a]pyrazine derived inhibitors of IGF-1R which features a substituted quinoline moiety at the C1 position and a cyclohexyl linking moiety at the C3 position. Lead optimization efforts which included the optimization of structure-activity relationships and drug metabolism and pharmacokinetic properties led to the identification of compound 9m, a potent, selective and orally bioavailable inhibitor of IGF-1R with in vivo efficacy in an IGF-driven mouse xenograft model.


Assuntos
Antineoplásicos/química , Benzimidazóis/química , Imidazóis/química , Inibidores de Proteínas Quinases/química , Pirazinas/química , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/farmacocinética , Pirazinas/uso terapêutico , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-Atividade , Transplante Heterólogo
7.
Org Lett ; 10(14): 2923-6, 2008 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-18576663

RESUMO

A general and efficient synthesis of 5-aryl imidazo[1,5- a]pyrazines by palladium-catalyzed coupling of the corresponding 8-substituted derivatives with aryl halides is described. The scope of this new reaction for the imidazo[1,5- a]pyrazine ring system was explored using three readily available 8-substituted precursors, X = NH2, NMe2, and OMe, as well as 8-aryl derivatives, X = Ar'. On the basis of these results as well as studies using a deuterated derivative, a Heck-like mechanism is proposed for this transformation.


Assuntos
Hidrocarbonetos Bromados/química , Imidazóis/síntese química , Paládio/química , Pirazinas/síntese química , Catálise , Técnicas de Química Combinatória , Imidazóis/química , Estrutura Molecular , Pirazinas/química , Estereoisomerismo
8.
Commun Biol ; 1: 100, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271980

RESUMO

The androgen receptor is a major driver of prostate cancer and inhibition of its transcriptional activity using competitive antagonists, such as enzalutamide remains a frontline therapy for prostate cancer management. However, the majority of patients eventually develop drug resistance. We propose that targeting the androgen receptor for degradation via Proteolysis Targeting Chimeras (PROTACs) will be a better therapeutic strategy for targeting androgen receptor signaling in prostate cancer cells. Here we perform a head-to-head comparison between a currently approved androgen receptor antagonist enzalutamide, and its PROTAC derivative, ARCC-4, across different cellular models of prostate cancer drug resistance. ARCC-4 is a low-nanomolar androgen receptor degrader able to degrade about 95% of cellular androgen receptors. ARCC-4 inhibits prostate tumor cell proliferation, degrades clinically relevant androgen receptor point mutants and unlike enzalutamide, retains antiproliferative effect in a high androgen environment. Thus, ARCC-4 exemplifies how protein degradation can address the drug resistance hurdles of enzalutamide.

9.
Org Lett ; 7(7): 1303-5, 2005 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-15787492

RESUMO

[reaction: see text] A total synthesis of (+)-peloruside A has been successfully achieved. The strategy was highlighted by a late stage aldol coupling of two complex fragments followed by an intramolecular hemi-ketal cyclization, a MOM group participated epoxide ring fragmentation reaction, and a highly selective methylation. This convergent route allows access to rationally designed analogues.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Lactonas/síntese química , Animais , Ciclização , Estrutura Molecular , Poríferos/química , Estereoisomerismo
10.
Org Lett ; 5(26): 4959-61, 2003 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-14682739

RESUMO

An efficient synthetic sequence toward the C8-C19 region of peloruside A has been developed. The route is highlighted by a selective electrophilic cyclization reaction, a single-step epoxide ring-opening/methylation sequence, and a stereoselective Mukaiyama aldol reaction. [reaction: see text]


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Lactonas/síntese química , Alquilação , Animais , Fenômenos Químicos , Físico-Química , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Poríferos , Estereoisomerismo
11.
Oncol Rev ; 7(1): e3, 2013 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-25992224

RESUMO

Based on over three decades of pre-clinical data, insulin-like growth factor-1 receptor (IGF-1R) signaling has gained recognition as a promoter of tumorogenesis, driving cell survival and proliferation in multiple human cancers. As a result, IGF-1R has been pursued as a target for cancer treatment. Early pioneering efforts targeting IGF-1R focused on highly selective monoclonal antibodies, with multiple agents advancing to clinical trials. However, despite some initial promising results, recent clinical disclosures have been less encouraging. Moreover, recent studies have revealed that IGF-1R participates in a dynamic and complex signaling network, interacting with additional targets and pathways thereof through various crosstalk and compensatory signaling mechanisms. Such mechanisms of bypass signaling help to shed some light on the decreased effectiveness of selective IGF-1R targeted therapies (e.g. monoclonal antibodies) and suggest that targeting multiple nodes within this signaling network might be necessary to produce a more effective therapeutic response. Additionally, such findings have led to the development of small molecule IGF-1R inhibitors which also co-inhibit additional targets such as insulin receptor and epidermal growth factor receptor. Such findings have helped to guide the design rationale of numerous drug combinations that are currently being evaluated in clinical trials.

12.
ACS Med Chem Lett ; 4(7): 627-31, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-24900721

RESUMO

This letter describes a series of small molecule inhibitors of IGF-1R with unique time-dependent binding kinetics and slow off-rates. Structure-activity and structure-kinetic relationships were elucidated and guided further optimizations within the series, culminating in compound 2. With an IGF-1R dissociative half-life (t 1/2) of >100 h, compound 2 demonstrated significant and extended PD effects in conjunction with tumor growth inhibition in xenograft models at a remarkably low and intermittent dose, which correlated with the observed in vitro slow off-rate properties.

13.
Future Med Chem ; 4(3): 315-28, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22393939

RESUMO

IGF-1R has been recognized as a major target in cancer drug discovery due to its strong implications in various stages of tumorigenesis based on accumulated preclinical data. Recent research on compensatory crosstalk between IGF-1R and insulin receptor (IR) signaling pathways suggests that targeting both IGF-1R and IR should result in a more therapeutically beneficial response, than targeting IGF-1R alone (e.g., IGF-1R-specific antibodies). These findings provided biological rationale and opened the door to the discovery of a variety of small-molecule dual IGF-1R and IR inhibitors. In this review we summarize the recent developments in this field, with a focus on binding modes and binding interactions of these inhibitors with IGF-1R and/or IR. Selectivity of these inhibitors has been discussed in this context as well. This is an important area to be discussed since one of the major challenges in kinase inhibitor drug discovery is to build an optimal selectivity profile based on biological rationale.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
14.
ACS Med Chem Lett ; 1(9): 510-5, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-24900240

RESUMO

This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacological activity of compound 9b, a potent, selective, well-tolerated, and orally bioavailable dual inhibitor of IGF-1R and IR with in vivo efficacy in tumor xenograft models, is discussed.

15.
Org Lett ; 11(22): 5118-21, 2009 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-19842687

RESUMO

Imidazo[1,5-a]pyrazines 1 undergo regioselective C3-metalation and C5/C3-dimetalation to afford a range of functionalized derivatives 2a-2g (Table 1 ), and 4a-4d (Table 2 ). Under similar conditions, the C3-methyl derivatives 2a and 5 undergo surprising regioselective C5-deprotonation to afford, after electrophile quench, products 4b and 6a-6p (Table 3 ), results that are rationalized by quantum mechanical calculations. Benzamide 7b, obtained from such metalation chemistry followed by Suzuki cross coupling, undergoes directed remote metalation-cyclization to afford 8, representing the hitherto unknown triazadibenzo[cd,f]azulen-7(6H)-one tricyclic ring system.


Assuntos
Imidazóis/síntese química , Metais/química , Pirazinas/síntese química , Ciclização , Imidazóis/química , Estrutura Molecular , Pirazinas/química , Teoria Quântica , Estereoisomerismo
16.
Org Biomol Chem ; 5(1): 61-4, 2007 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-17164907

RESUMO

A highly effective one-pot Friedländer quinoline synthesis using inexpensive reagents has been developed. o-Nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of catalytic HCl (aq.) and subsequently condensed in situ with aldehydes or ketones to form mono- or di-substituted quinolines in high yields (66-100%).


Assuntos
Aldeídos/química , Benzaldeídos/química , Quinolinas/síntese química , Ferro/química , Cetonas/química , Estrutura Molecular , Oxirredução , Quinolinas/química
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