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1.
Cell Chem Biol ; 28(2): 134-147.e14, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33086052

RESUMO

Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Quinase 9 Dependente de Ciclina/antagonistas & inibidores , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores Androgênicos/genética , Transcrição Gênica/efeitos dos fármacos , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Linhagem Celular Tumoral , Quinase 9 Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Neoplasias de Próstata Resistentes à Castração/genética , Inibidores de Proteínas Quinases/uso terapêutico
2.
J Chem Inf Model ; 59(5): 2046-2062, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-30817167

RESUMO

At the onset of a drug discovery program, the goal is to identify novel compounds with appropriate chemical features that can be taken forward as lead series. Here, we describe three prospective case studies, Bruton Tyrosine Kinase (BTK), RAR-Related Orphan Receptor γ t (RORγt), and Human Leukocyte Antigen DR isotype (HLA-DR) to illustrate the positive impact of high throughput virtual screening (HTVS) on the successful identification of novel chemical series. Each case represents a project with a varying degree of difficulty due to the amount of structural and ligand information available internally or in the public domain to utilize in the virtual screens. We show that HTVS can be effectively employed to identify a diverse set of potent hits for each protein system even when the gold standard, high resolution structural data or ligand binding data for benchmarking, is not available.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/métodos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/química , Indústria Farmacêutica , Antígenos HLA-DR/química , Antígenos HLA-DR/metabolismo , Humanos , Modelos Moleculares , Receptores Nucleares Órfãos/química , Receptores Nucleares Órfãos/metabolismo , Conformação Proteica , Inibidores de Proteínas Quinases/farmacologia , Fatores de Tempo , Interface Usuário-Computador
4.
J Med Chem ; 55(3): 1402-17, 2012 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-22239465

RESUMO

The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.


Assuntos
Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/síntese química , Indenos/síntese química , Transtornos Parkinsonianos/tratamento farmacológico , Pirimidinas/síntese química , Receptor A2A de Adenosina/metabolismo , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/farmacologia , Administração Oral , Animais , Desenho de Fármacos , Feminino , Indenos/farmacocinética , Indenos/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transtornos Parkinsonianos/induzido quimicamente , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
5.
J Med Chem ; 53(22): 8104-15, 2010 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-20973483

RESUMO

The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.


Assuntos
Antagonistas do Receptor A1 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antiparkinsonianos/síntese química , Indenos/síntese química , Doença de Parkinson/metabolismo , Pirimidinas/síntese química , Receptor A2A de Adenosina/fisiologia , Antagonistas do Receptor A1 de Adenosina/farmacocinética , Antagonistas do Receptor A1 de Adenosina/farmacologia , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Antagonistas do Receptor A2 de Adenosina/farmacologia , Administração Oral , Animais , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Callithrix , Modelos Animais de Doenças , Feminino , Indenos/farmacocinética , Indenos/farmacologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley
7.
Bioorg Med Chem Lett ; 20(9): 2868-71, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20338760

RESUMO

Two reactive metabolites were identified in vivo for the dual A(2A)/A(1) receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.


Assuntos
Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Neurotransmissores/química , Pirimidinas/química , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Camundongos , Neurotransmissores/síntese química , Neurotransmissores/uso terapêutico , Pirimidinas/síntese química , Pirimidinas/uso terapêutico , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 14(12): 3245-50, 2004 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-15149684

RESUMO

A novel series of acyclic 3-(7-azaindolyl)-4-(aryl/heteroaryl)maleimides was synthesized and evaluated for activity against GSK-3beta and selectivity versus PKC-betaII, as well as a broad panel of protein kinases. Compounds 14 and 17c potently inhibited GSK-3beta (IC(50)=7 and 26 nM, respectively) and exhibited excellent selectivity over PKC-betaII (325 and >385-fold, respectively). Compound 17c was also highly selective against 68 other protein kinases. In a cell-based functional assay, both 14 and 17c effectively increased glycogen synthase activity by inhibiting GSK-3beta.


Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Maleimidas/química , Inibidores de Proteínas Quinases/química , Linhagem Celular , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Maleimidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia
9.
Bioorg Med Chem ; 12(12): 3167-85, 2004 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-15158785

RESUMO

Two approaches were developed to synthesize the novel 7-azaindolyl-heteroarylmaleimides. The first approach was based upon the palladium-catalyzed Suzuki cross-coupling or Stille cross-coupling of 2-chloro-maleimide 5 with various arylboronic acids or arylstannanes. The second approach was based upon the condensation of ethyl 7-azaindolyl-3-glyoxylate 12 with various acetamides. The hydroxypropyl-substituted 7-azaindolylmaleimide template was first used to screen different heteroaryls attached to the maleimide. Replacement of hydroxypropyl with different chain lengths and different functional groups were studied next. Many compounds synthesized were demonstrated to have high potency at GSK-3beta, good GS activity in HEK293 cells and good to excellent metabolic stability in human liver microsomes. Three representative compounds (21, 33, and 34) were demonstrated to have good selectivity against a panel of 80 kinase assays. Among them, compound 33 exhibited very weak inhibitions at the other 79 kinase assays, and behaved as a highly selective GSK-3beta inhibitor.


Assuntos
Compostos Aza/síntese química , Compostos Aza/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Maleimidas/química , Maleimidas/farmacologia , Animais , Compostos Aza/química , Linhagem Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Maleimidas/síntese química , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Coelhos , Especificidade por Substrato
10.
Bioorg Med Chem ; 12(5): 1239-55, 2004 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-14980636

RESUMO

Palladium catalyzed cross-coupling reactions were used to synthesize two key intermediates 3 and 5 that resulted in the synthesis of novel series of macrocyclic bis-7-azaindolylmaleimides. Among the three series of macrocycles, the oxygen atom and thiophene containing linkers yielded molecules with higher inhibitory potency at GSK-3 beta (K(i)=0.011-0.079 microM) while the nitrogen atom containing linkers yielded molecules with lower potency (K(i)=0.150->1 microM). Compound 33 and 36 displayed 1-2 orders of magnitude selectivity at GSK-3 beta against CDK2, PKC beta II, Rsk3 and little or no inhibitions to the other 62 protein kinases. Compound 46 was at least 100-fold more selective towards GSK-3 beta than PKC beta II, and it had little or no activity against a panel of 65 protein kinases, almost behaved as a GSK-3 beta 'specific inhibitor'. All three compounds showed good potency in GS assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3 beta selectivity of azaindolylmaleimides. The high selectivity, inhibitory potency and cellular activities of these non-crown-ether typed molecules may provide them as a valuable pharmacological tools in elucidating the complex roles of GSK-3 beta in cell signaling pathways and the potential usage for the treatment of elevated level of GSK-3 beta involved diseases.


Assuntos
Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Maleimidas/síntese química , Maleimidas/farmacologia , Sequência de Aminoácidos , Linhagem Celular , Simulação por Computador , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta , Humanos , Maleimidas/química , Proteínas Quinases/química , Proteínas Quinases/classificação , Proteínas Quinases/efeitos dos fármacos , Alinhamento de Sequência , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 14(5): 1155-9, 2004 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-14980655

RESUMO

The use of a multiplex mimetic assay led us to identify 1,4-dihydropyrimidines with potent and selective calcitonin receptor mimetic activity. Subsequent modification of the dihydropyrimidine scaffold led to a series of molecules that were efficacious in a neonatal mouse calvaria in vitro model. Dihydropyrimidine 5h, in particular, was identified as a calcitonin mimetic (EC(50)=6 microM), active in-vivo in the Weanling rat model when administered subcutaneously.


Assuntos
Calcitonina/química , Calcitonina/fisiologia , Di-Hidropiridinas/química , Mimetismo Molecular/fisiologia , Pirimidinas/química , Animais , Calcitonina/urina , Linhagem Celular , Di-Hidropiridinas/farmacologia , Di-Hidropiridinas/urina , Humanos , Pirimidinas/farmacologia , Pirimidinas/urina , Ratos
12.
J Biomol Screen ; 8(4): 439-46, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-14567796

RESUMO

Stimulation of a cell with insulin initiates a signal transduction cascade that results in cellular activities that include phosphorylation of the receptor itself. Measurement of the degree of phosphorylation can serve as a marker for receptor activation. Receptor phosphorylation has been measured using Western blot analysis, which is very low throughput and not easily quantifiable. The goal of this project was to develop a cell-based assay to measure receptor phosphorylation in high throughput. This report describes a cell-based assay for insulin receptor phosphorylation that is robust and amenable to high-volume screening in a microwell format.


Assuntos
Transferência Ressonante de Energia de Fluorescência/métodos , Insulina/metabolismo , Receptor de Insulina/metabolismo , Animais , Células CHO , Cricetinae , Indicadores e Reagentes , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais
13.
J Med Chem ; 46(19): 4021-31, 2003 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-12954055

RESUMO

Attempts to design the macrocyclic maleimides as selective protein kinase C gamma inhibitors led to the unexpected discovery of a novel series of potent and highly selective glycogen synthase kinase-3beta (GSK-3beta) inhibitors. Palladium-catalyzed cross-coupling reactions were used to synthesize the key intermediates 17 and 22 that resulted in the synthesis of novel macrocycles. All three macrocyclic series (bisindolyl-, mixed 7-azaindoleindolyl-, and bis-7-azaindolylmaleimides) were found to have submicromolar inhibitory potency at GSK-3beta with various degrees of selectivity toward other protein kinases. To gain the inhibitory potency at GSK-3beta, the ring sizes of these macrocycles may play a major role. To achieve the selectivity at GSK-3beta, the additional nitrogen atoms in the indole rings may contribute to a significant degree. Overall, the bis-7-azaindolylmaleimides 28 and 29 exhibited little or no inhibitions to a panel of 50 protein kinases. Compound 29 almost behaved as a GSK-3beta specific inhibitor. Both 28 and 29 displayed good potency in GS cell-based assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3beta selectivity of azaindolylmaleimides.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Éteres Cíclicos/síntese química , Éteres Cíclicos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Maleimidas/síntese química , Maleimidas/farmacologia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Células Cultivadas , Desenho de Fármacos , Éteres Cíclicos/química , Quinase 3 da Glicogênio Sintase/metabolismo , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Maleimidas/química , Modelos Moleculares , Dados de Sequência Molecular , Inibidores de Proteínas Quinases , Proteínas Quinases/metabolismo , Ratos , Alinhamento de Sequência , Relação Estrutura-Atividade , Especificidade por Substrato
14.
Bioorg Med Chem Lett ; 13(18): 3049-53, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12941331

RESUMO

Efficient methods were developed to synthesize a novel series of macrocyclic bisindolylmaleimides containing linkers with multiple heteroatoms. Potent inhibitors (single digit nanomolar IC(50)) for PKC-beta and GSK-3beta were identified, and compounds showed good selectivity over PKC-alpha, -gamma, -delta, -epsilon, and -zeta. Representative compound 5a also had high selectivity in a screening panel of 10 other protein kinases. In cell-based functional assays, several compounds effectively blocked interleukin-8 release induced by PKC-betaII and increased glycogen synthase activity by inhibiting GSK-3beta.


Assuntos
Indóis/síntese química , Maleimidas/síntese química , Proteína Quinase C/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular , Ciclização , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta , Humanos , Indóis/farmacologia , Concentração Inibidora 50 , Isoenzimas/síntese química , Isoenzimas/farmacologia , Maleimidas/farmacologia , Proteína Quinase C beta , Relação Estrutura-Atividade
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