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1.
Mol Cancer Ther ; 20(12): 2317-2328, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34583982

RESUMO

The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome. JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent antiproliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myelogenous leukemia samples, the presence of splicing factor mutations correlated with a higher ex vivo sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models in vivo, with once-daily or intermittent oral-dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity-driven tumors.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteína-Arginina N-Metiltransferases/efeitos dos fármacos , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Animais , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Pirimidinas/farmacologia , Pirróis/farmacologia
2.
Science ; 363(6431)2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30846569

RESUMO

Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted three-dimensional cell culture of fully differentiated human bronchial epithelial cells. Cocrystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.


Assuntos
Anticorpos Neutralizantes/química , Materiais Biomiméticos/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Influenza Humana/prevenção & controle , Piperazinas/farmacologia , Piridinas/farmacologia , Tetrazóis/farmacologia , Inibidores de Proteínas Virais de Fusão/farmacologia , Internalização do Vírus/efeitos dos fármacos , Administração Oral , Animais , Materiais Biomiméticos/administração & dosagem , Materiais Biomiméticos/farmacocinética , Brônquios/virologia , Células Cultivadas , Cães , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Humanos , Células Madin Darby de Rim Canino , Camundongos , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Mucosa Respiratória/virologia , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética , Inibidores de Proteínas Virais de Fusão/administração & dosagem , Inibidores de Proteínas Virais de Fusão/farmacocinética
4.
Bioorg Med Chem Lett ; 28(13): 2320-2323, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29853330

RESUMO

In this study, affinities and activities of derivatized analogues of Dmt-dermorphin[1-4] (i.e. Dmt-d-Ala-Phe-GlyNH2, Dmt = 2',6'-dimethyl-(S)-tyrosine) for the µ opioid receptor (MOP) and δ opioid receptor (DOP) were evaluated using radioligand binding studies, functional cell-based assays and isolated organ bath experiments. By means of solid-phase or solution-phase Suzuki-Miyaura cross-couplings, various substituted regioisomers of the phenylalanine moiety in position 3 of the sequence were prepared. An 18-membered library of opioid tetrapeptides was generated via screening of the chemical space around the Phe3 side chain. These substitutions modulated bioactivity, receptor subtype selectivity and highly effective ligands with subnanomolar binding affinities, contributed to higher functional activities and potent analgesic actions. In search of selective peptidic ligands, we show here that the Suzuki-Miyaura reaction is a versatile and robust tool which could also be deployed elsewhere.


Assuntos
Analgésicos Opioides/uso terapêutico , Oligopeptídeos/uso terapêutico , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Analgésicos Opioides/farmacologia , Animais , Cobaias , Células HEK293 , Humanos , Ligantes , Masculino , Camundongos , Estrutura Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Ratos Sprague-Dawley
5.
Science ; 358(6362): 496-502, 2017 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-28971971

RESUMO

Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114). The optimized peptides exhibit nanomolar affinity and neutralization against influenza A group 1 viruses, including the 2009 H1N1 pandemic and avian H5N1 strains. The peptide inhibitors bind to the highly conserved stem epitope and block the low pH-induced conformational rearrangements associated with membrane fusion. These peptidic compounds and their advantageous biological properties should accelerate the development of new small molecule- and peptide-based therapeutics against influenza virus.


Assuntos
Antivirais/química , Desenho de Fármacos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Peptídeos Cíclicos/química , Internalização do Vírus/efeitos dos fármacos , Animais , Anticorpos Neutralizantes/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Regiões Determinantes de Complementaridade/química , Cristalografia por Raios X , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Conformação Proteica
6.
Org Lett ; 16(10): 2622-5, 2014 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-24805161

RESUMO

A simple and scalable one-pot biotransformation enables direct access to L-halotryptophans, including L-7-iodotryptophan, from the corresponding haloindoles. The biotransformation utilizes an easy to prepare bacterial cell lysate that may be stored as the lyophilizate for several months and utilized as a catalyst as and when required.


Assuntos
Hidrocarbonetos Iodados/química , Hidrocarbonetos Iodados/síntese química , Indóis/química , Indóis/síntese química , Serina/química , Triptofano/análogos & derivados , Triptofano/síntese química , Biotransformação , Catálise , Estrutura Molecular , Estereoisomerismo , Triptofano/química , Triptofano Sintase/metabolismo
7.
Bioorg Med Chem Lett ; 23(1): 310-7, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23177258

RESUMO

The design and synthesis of novel HIV-1 protease inhibitors (PIs) (1-22), which display high potency against HIV-1 wild-type and multi-PI-resistant HIV-mutant clinical isolates, is described. Lead optimization was initiated from compound 1, a Phe-Phe hydroxyethylene peptidomimetic PI, and was directed towards the discovery of new PIs suitable for a long-acting (LA) injectable drug application. Introducing a heterocyclic 6-methoxy-3-pyridinyl or a 6-(dimethylamino)-3-pyridinyl moiety (R(3)) at the para-position of the P1' benzyl fragment generated compounds with antiviral potency in the low single digit nanomolar range. Halogenation or alkylation of the metabolic hot spots on the various aromatic rings resulted in PIs with high stability against degradation in human liver microsomes and low plasma clearance in rats. Replacing the chromanolamine moiety (R(1)) in the P2 protease binding site by a cyclopentanolamine or a cyclohexanolamine derivative provided a series of high clearance PIs (16-22) with EC(50)s on wild-type HIV-1 in the range of 0.8-1.8 nM. PIs 18 and 22, formulated as nanosuspensions, showed gradual but sustained and complete release from the injection site over two months in rats, and were therefore identified as interesting candidates for a LA injectable drug application for treating HIV/AIDS.


Assuntos
Carbamatos/síntese química , Dipeptídeos/síntese química , Desenho de Fármacos , Inibidores da Protease de HIV/síntese química , Protease de HIV/química , HIV-1/enzimologia , Piridinas/síntese química , Alquilação , Animais , Carbamatos/química , Carbamatos/farmacocinética , Dipeptídeos/química , Dipeptídeos/farmacocinética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacocinética , Meia-Vida , Halogenação , Humanos , Microssomos Hepáticos/metabolismo , Piridinas/química , Piridinas/farmacocinética , Ratos , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 22(15): 4998-5002, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22765892

RESUMO

A new class of benzoxazole and benzothiazole amide derivatives exhibiting potent CYP3A4 inhibiting properties was identified. Extensive lead optimization was aimed at improving the CYP3A4 inhibitory properties as well as overall ADME profile of these amide derivatives. This led to the identification of thiazol-5-ylmethyl (2S,3R)-4-(2-(ethyl(methyl)amino)-N-isobutylbenzo[d]oxazole-6-carboxamido)-3-hydroxy-1-phenylbutan-2-ylcarbamate (C1) as a lead candidate for this class. This compound together with structurally similar analogues demonstrated excellent 'boosting' properties when tested in dogs. These findings warrant further evaluation of their properties in an effort to identify valuable alternatives to Ritonavir as pharmacokinetic enhancers.


Assuntos
Amidas/química , Benzotiazóis/química , Benzoxazóis/química , Inibidores da Protease de HIV/química , Amidas/síntese química , Amidas/farmacocinética , Animais , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Cães , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacocinética , HIV-1/enzimologia , Meia-Vida , Humanos , Ratos , Relação Estrutura-Atividade
9.
J Steroid Biochem Mol Biol ; 103(3-5): 206-12, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17218098

RESUMO

During a 20-year collaboration the laboratories of UGent and KU Leuven have developed different series of Vitamin D analogs characterized by structural modifications in the central CD-ring system. Modifications have first involved the introduction of substituents at C11 and the epimerization at C14, and subsequently more drastic changes consisting in both ring deletion and enlargement relative to the natural CD-ring system. Lately, the focus has shifted towards the synthesis of analogs featuring a symmetrical CD-ring core. As an illustration two different series are presented.


Assuntos
Calcitriol/análogos & derivados , Calcitriol/química , Calcitriol/biossíntese , Calcitriol/síntese química , Desenho de Fármacos , Humanos , Estrutura Molecular
10.
Org Lett ; 8(19): 4247-50, 2006 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-16956198

RESUMO

A novel series of analogues of calcitriol (1) is developed featuring a spirocyclic central core resulting from C18/C21-connection and C15/C16-deletion (2a, 2b). The synthesis of the key intermediate involves an Eschenmoser rearrangement of an enantiomerically pure bromo-substituted cyclohexenol.


Assuntos
Alcanos/química , Calcitriol/síntese química , Calcitriol/química , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Estereoisomerismo
11.
Bioorg Med Chem Lett ; 14(15): 3889-92, 2004 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-15225691

RESUMO

The synthesis and biological activity of novel CD-ring modified analogues of 22-oxa-1alpha,25-dihydroxyvitamin D(3), lacking the D-ring and featuring a connection between C-18 and C-21 (spiro[5.5]undecane CF-ring analogues), is described. The central ring system is conveniently synthesised from an achiral intermediate. The analogues have marginal binding affinity for the nVDR and possess low to moderate genomic activity.


Assuntos
Calcitriol/análogos & derivados , Calcitriol/farmacologia , Calcitriol/síntese química , Calcitriol/química , Regulação da Expressão Gênica/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Relação Estrutura-Atividade
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