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1.
Clin Cancer Res ; 23(22): 6969-6981, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28855357

RESUMO

Purpose:RUNX1-mutated (RUNX1mut) acute myeloid leukemia (AML) is associated with adverse outcome, highlighting the urgent need for a better genetic characterization of this AML subgroup and for the design of efficient therapeutic strategies for this disease. Toward this goal, we further dissected the mutational spectrum and gene expression profile of RUNX1mut AML and correlated these results to drug sensitivity to identify novel compounds targeting this AML subgroup.Experimental Design: RNA-sequencing of 47 RUNX1mut primary AML specimens was performed and sequencing results were compared to those of RUNX1 wild-type samples. Chemical screens were also conducted using RUNX1mut specimens to identify compounds selectively affecting the viability of RUNX1mut AML.Results: We show that samples with no remaining RUNX1 wild-type allele are clinically and genetically distinct and display a more homogeneous gene expression profile. Chemical screening revealed that most RUNX1mut specimens are sensitive to glucocorticoids (GCs) and we confirmed that GCs inhibit AML cell proliferation through their interaction with the glucocorticoid receptor (GR). We observed that specimens harboring RUNX1 mutations expected to result in low residual RUNX1 activity are most sensitive to GCs, and that coassociating mutations as well as GR levels contribute to GC sensitivity. Accordingly, acquired glucocorticoid sensitivity was achieved by negatively regulating RUNX1 expression in human AML cells.Conclusions: Our findings show the profound impact of RUNX1 allele dosage on gene expression profile and glucocorticoid sensitivity in AML, thereby opening opportunities for preclinical testing which may lead to drug repurposing and improved disease characterization. Clin Cancer Res; 23(22); 6969-81. ©2017 AACR.


Assuntos
Alelos , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Resistencia a Medicamentos Antineoplásicos/genética , Dosagem de Genes , Glucocorticoides/farmacologia , Leucemia Mieloide Aguda/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Regulação Leucêmica da Expressão Gênica , Inativação Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade
2.
Science ; 345(6203): 1509-12, 2014 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-25237102

RESUMO

The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.


Assuntos
Sangue Fetal/efeitos dos fármacos , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Indóis/farmacologia , Pirimidinas/farmacologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Regeneração/efeitos dos fármacos , Animais , Técnicas de Cultura de Células , Sangue Fetal/citologia , Sangue Fetal/fisiologia , Terapia Genética/métodos , Hematopoese/fisiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/fisiologia , Humanos , Hospedeiro Imunocomprometido , Indóis/química , Camundongos , Pirimidinas/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
3.
Nat Methods ; 11(4): 436-42, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24562423

RESUMO

Leukemic stem cells (LSCs) are considered a major cause of relapse in acute myeloid leukemia (AML). Defining pathways that control LSC self-renewal is crucial for a better understanding of underlying mechanisms and for the development of targeted therapies. However, currently available culture conditions do not prevent spontaneous differentiation of LSCs, which greatly limits the feasibility of cell-based assays. To overcome these constraints we conducted a high-throughput chemical screen and identified small molecules that inhibit differentiation and support LSC activity in vitro. Similar to reports with cord blood stem cells, several of these compounds suppressed the aryl-hydrocarbon receptor (AhR) pathway, which we show to be inactive in vivo and rapidly activated ex vivo in AML cells. We also identified a compound, UM729, that collaborates with AhR suppressors in preventing AML cell differentiation. Together, these findings provide newly defined culture conditions for improved ex vivo culture of primary human AML cells.


Assuntos
Adenina/análogos & derivados , Técnicas de Cultura de Células/métodos , Indóis/farmacologia , Leucemia/metabolismo , Células-Tronco Neoplásicas/fisiologia , Pirimidinas/farmacologia , Adenina/farmacologia , Meios de Cultura Livres de Soro , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Leucemia Mieloide Aguda , Estrutura Molecular
4.
Bioorg Med Chem Lett ; 24(5): 1294-8, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24513044

RESUMO

Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.


Assuntos
Compostos de Fenilureia/química , Inibidores da Agregação de Plaquetas/química , Antagonistas do Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Tiazóis/química , Ureia/análogos & derivados , Administração Oral , Animais , Cães , Meia-Vida , Macaca fascicularis , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacocinética , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Trombose/tratamento farmacológico , Ureia/farmacocinética , Ureia/farmacologia , Ureia/uso terapêutico
5.
Bioorg Med Chem Lett ; 23(24): 6825-8, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24269480

RESUMO

A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional activities, as well as improved aqueous solubility. Among them, the piperidine 4a showed the best overall profile with favorable PK parameters.


Assuntos
Aminas/química , Agonistas do Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Ureia/análogos & derivados , Difosfato de Adenosina/farmacologia , Aminas/síntese química , Aminas/farmacocinética , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Piperidinas/química , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacocinética , Ligação Proteica , Agonistas do Receptor Purinérgico P2Y/síntese química , Agonistas do Receptor Purinérgico P2Y/farmacocinética , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacocinética
6.
J Med Chem ; 56(22): 9275-95, 2013 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-24164581

RESUMO

Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.


Assuntos
Desenho de Drogas , Conformação Molecular , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Receptores Purinérgicos P2Y1/metabolismo , Compostos de Espiro/farmacologia , Compostos de Espiro/farmacocinética , Ureia/farmacologia , Ureia/farmacocinética , Animais , Disponibilidade Biológica , Humanos , Indóis/química , Modelos Moleculares , Compostos de Fenilureia/química , Compostos de Fenilureia/metabolismo , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y1/química , Homologia de Sequência de Aminoácidos , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Ureia/química , Ureia/metabolismo
7.
Bioorg Med Chem Lett ; 23(12): 3519-22, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23668989

RESUMO

Five-membered-ring heterocyclic urea mimics have been found to be potent and selective antagonists of the P2Y1 receptor. SAR of the various heterocyclic replacements is presented, as well as side-chain SAR of the more potent thiadiazole ring system which leads to thiadiazole 4c as a new antiplatelet agent.


Assuntos
Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y1/química , Tiadiazóis/química , Tiadiazóis/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Humanos , Cinética , Ligação Proteica , Relação Estrutura-Atividade , Ureia/química
8.
Bioorg Med Chem Lett ; 18(9): 2985-9, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18395443

RESUMO

We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.


Assuntos
Inibidores da Angiogênese/farmacologia , Desenho de Drogas , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirróis/farmacologia , Triazinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Animais , Linhagem Celular , Inibidores do Citocromo P-450 CYP3A , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Pirróis/síntese química , Relação Estrutura-Atividade , Triazinas/síntese química , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Org Lett ; 5(26): 5023-5, 2003 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-14682755

RESUMO

Two routes describing the preparation of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (4a) from 1H-pyrrolo[2,3-b]pyridine N-oxide (1) are presented. Regioselective fluorination was achieved using either the Balz-Schiemann reaction or lithium-halogen exchange. [reaction: see text]

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