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1.
Nat Commun ; 12(1): 3332, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099697

RESUMO

Pre-mRNA splicing is a key controller of human gene expression. Disturbances in splicing due to mutation lead to dysregulated protein expression and contribute to a substantial fraction of human disease. Several classes of splicing modulator compounds (SMCs) have been recently identified and establish that pre-mRNA splicing represents a target for therapy. We describe herein the identification of BPN-15477, a SMC that restores correct splicing of ELP1 exon 20. Using transcriptome sequencing from treated fibroblast cells and a machine learning approach, we identify BPN-15477 responsive sequence signatures. We then leverage this model to discover 155 human disease genes harboring ClinVar mutations predicted to alter pre-mRNA splicing as targets for BPN-15477. Splicing assays confirm successful correction of splicing defects caused by mutations in CFTR, LIPA, MLH1 and MAPT. Subsequent validations in two disease-relevant cellular models demonstrate that BPN-15477 increases functional protein, confirming the clinical potential of our predictions.


Assuntos
Aprendizado Profundo , Marcação de Genes/métodos , Splicing de RNA , Animais , Biologia Computacional , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Éxons , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Proteína 1 Homóloga a MutL/genética , Mutação , Fenetilaminas/administração & dosagem , Piridazinas/administração & dosagem , Esterol Esterase/genética , Transcriptoma , Proteínas tau/genética
2.
Bioorg Med Chem ; 28(22): 115734, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-33007551

RESUMO

The evolution of gamma-secretase modulators (GSMs) through the introduction of novel heterocycles with the goal of aligning activity for reducing the levels of Aß42 and properties consistent with a drug-like molecule are described. The insertion of a methoxypyridine motif within the tetracyclic scaffold provided compounds with improved activity for arresting Aß42 production as well as improved properties, including solubility. In vivo pharmacokinetic analysis demonstrated that several compounds within the novel series were capable of crossing the BBB and accessing the therapeutic target. Treatment with methoxypyridine-derived compound 64 reduced Aß42 levels in the plasma of J20 mice, in addition to reducing Aß42 levels in the plasma and brain of Tg2576 mice.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/análise , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 26(16): 3928-37, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27426299

RESUMO

The design and construction of a series of novel aminothiazole-derived γ-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. γ-Secretase modulator 28 displayed good activity for in vitro inhibition of Aß42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Desenho de Fármacos , Tiazóis/química , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Meia-Vida , Humanos , Cinética , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Ratos , Solubilidade , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética
4.
Bioorg Med Chem ; 23(12): 2810-8, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25703307

RESUMO

The cell division cycle 25B dual specificity phosphatase (Cdc25B) regulates the normal progression of the mammalian cell cycle by dephosphorylating and activating cyclin-dependent kinase (Cdk) complexes, particularly in response to DNA damage. Elevated Cdc25B levels enable a bypass of normal cell cycle checkpoints, and the overexpression of Cdc25B has been linked to a variety of human cancers. Thus, Cdc25B is an attractive target for the development of anticancer therapeutics. Herein we describe the synthesis and biological evaluation of a series of non-quinoid inhibitors of Cdc25B containing the 3-aminoisoquinolin-1(2H)-one pharmacophore. In addition to several strategies that address specific substitution patterns on isoquinolines, we have applied a regioselective Pd-catalyzed cross-coupling methodology to synthesize a new lead structure, 6-(3-aminophenyl)-3-(phenylamino)isoquinolin-1(2H)-one (13), which proved to be a reversible, competitive Cdc25B inhibitor with a Ki of 1.9µM. Compound 13 prevented human cancer cell growth and blocked Cdc25B-mediated mitotic checkpoint bypass. Molecular docking studies support binding near the catalytic site.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Fosfatases cdc25/antagonistas & inibidores , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Humanos , Isoquinolinas/síntese química , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Fosfatases cdc25/química , Fosfatases cdc25/metabolismo
5.
Assay Drug Dev Technol ; 7(3): 250-65, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19530895

RESUMO

The University of Pittsburgh Molecular Library Screening Center (Pittsburgh, PA) conducted a screen with the National Institutes of Health compound library for inhibitors of in vitro cell division cycle 25 protein (Cdc25) B activity during the pilot phase of the Molecular Library Screening Center Network. Seventy-nine (0.12%) of the 65,239 compounds screened at 10 muM met the active criterion of > or =50% inhibition of Cdc25B activity, and 25 (31.6%) of these were confirmed as Cdc25B inhibitors with 50% inhibitory concentration (IC(50)) values <50 microM. Thirteen of the Cdc25B inhibitors were represented by singleton chemical structures, and 12 were divided among four clusters of related structures. Thirteen (52%) of the Cdc25B inhibitor hits were quinone-based structures. The Cdc25B inhibitors were further characterized in a series of in vitro secondary assays to confirm their activity, to determine their phosphatase selectivity against two other dual-specificity phosphatases, mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-3, and to examine if the mechanism of Cdc25B inhibition involved oxidation and inactivation. Nine Cdc25B inhibitors did not appear to affect Cdc25B through a mechanism involving oxidation because they did not generate detectable amounts of H(2)O(2) in the presence of dithiothreitol, and their Cdc25B IC(50) values were not significantly affected by exchanging the dithiothreitol for beta-mercaptoethanol or reduced glutathione or by adding catalase to the assay. Six of the nonoxidative hits were selective for Cdc25B inhibition versus MKP-1 and MKP-3, but only the two bisfuran-containing hits, PubChem substance identifiers 4258795 and 4260465, significantly inhibited the growth of human MBA-MD-435 breast and PC-3 prostate cancer cell lines. To confirm the structure and biological activity of 4260465, the compound was resynthesized along with two analogs. Neither of the substitutions to the two analogs was tolerated, and only the resynthesized hit 26683752 inhibited Cdc25B activity in vitro (IC(50) = 13.83 +/- 1.0 microM) and significantly inhibited the growth of the MBA-MD-435 breast and PC-3 prostate cancer cell lines (IC(50) = 20.16 +/- 2.0 microM and 24.87 +/- 2.25 microM, respectively). The two bis-furan-containing hits identified in the screen represent novel nonoxidative Cdc25B inhibitor chemotypes that block tumor cell proliferation. The availability of non-redox active Cdc25B inhibitors should provide valuable tools to explore the inhibition of the Cdc25 phosphatases as potential mono- or combination therapies for cancer.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fosfatases cdc25/antagonistas & inibidores , Antineoplásicos/química , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Fosfatase 1 de Especificidade Dupla/antagonistas & inibidores , Fosfatase 1 de Especificidade Dupla/biossíntese , Fosfatase 1 de Especificidade Dupla/isolamento & purificação , Fosfatase 6 de Especificidade Dupla/antagonistas & inibidores , Fosfatase 6 de Especificidade Dupla/biossíntese , Fosfatase 6 de Especificidade Dupla/isolamento & purificação , Inibidores Enzimáticos/química , Feminino , Humanos , Peróxido de Hidrogênio/química , Indicadores e Reagentes , Masculino , Fosfatases da Proteína Quinase Ativada por Mitógeno/antagonistas & inibidores , Fosfatases da Proteína Quinase Ativada por Mitógeno/biossíntese , Fosfatases da Proteína Quinase Ativada por Mitógeno/isolamento & purificação , National Institutes of Health (U.S.) , Oxirredução , Bibliotecas de Moléculas Pequenas , Estados Unidos
7.
Org Lett ; 6(1): 103-6, 2004 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-14703361

RESUMO

[reaction: see text] A novel approach toward the synthesis of the triene portion of the biologically active polyketide apoptolidin is described. The use of an iterative thionyl chloride rearrangement/oxidation sequence to construct trisubstituted olefins is explored.


Assuntos
Macrolídeos/síntese química , Alcenos/química , Modelos Químicos , Estrutura Molecular , Estereoisomerismo
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