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1.
J Med Chem ; 59(11): 5221-37, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27167172

RESUMO

Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic-pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.


Assuntos
4-Aminopiridina/análogos & derivados , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , 4-Aminopiridina/síntese química , 4-Aminopiridina/química , 4-Aminopiridina/farmacologia , Quinase 1 do Ponto de Checagem/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazinas/síntese química , Pirazinas/química , Relação Estrutura-Atividade
2.
Oncotarget ; 7(3): 2329-42, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26295308

RESUMO

CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition.


Assuntos
4-Aminopiridina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quinase 1 do Ponto de Checagem/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirazinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , 4-Aminopiridina/farmacocinética , 4-Aminopiridina/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2 , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Quinase do Ponto de Checagem 2/antagonistas & inibidores , Quinases Ciclina-Dependentes/antagonistas & inibidores , Dano ao DNA/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Células HT29 , Humanos , Irinotecano , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos Transgênicos , Pirazinas/farmacocinética , Gencitabina
3.
J Med Chem ; 55(22): 10229-40, 2012 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-23082860

RESUMO

Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment-based drug design and optimized for CHK1 potency and high selectivity using a cell-based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/química , Pirimidinas/farmacologia , Administração Oral , Aminopiridinas/síntese química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Quinase 1 do Ponto de Checagem , Criança , Neoplasias do Colo/enzimologia , Dano ao DNA/efeitos dos fármacos , Desenho de Fármacos , Humanos , Camundongos , Camundongos Nus , Camundongos Transgênicos , Proteína Proto-Oncogênica N-Myc , Neuroblastoma/enzimologia , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/metabolismo , Pirimidinas/síntese química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Clin Cancer Res ; 18(20): 5650-61, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22929806

RESUMO

PURPOSE: Many tumors exhibit defective cell-cycle checkpoint control and increased replicative stress. CHK1 is critically involved in the DNA damage response and maintenance of replication fork stability. We have therefore discovered a novel potent, highly selective, orally active ATP-competitive CHK1 inhibitor, CCT244747, and present its preclinical pharmacology and therapeutic activity. EXPERIMENTAL DESIGN: Cellular CHK1 activity was assessed using an ELISA assay, and cytotoxicity a SRB assay. Biomarker modulation was measured using immunoblotting, and cell-cycle effects by flow cytometry analysis. Single-agent oral CCT244747 antitumor activity was evaluated in a MYCN-driven transgenic mouse model of neuroblastoma by MRI and in genotoxic combinations in human tumor xenografts by growth delay. RESULTS: CCT244747 inhibited cellular CHK1 activity (IC(50) 29-170 nmol/L), significantly enhanced the cytotoxicity of several anticancer drugs, and abrogated drug-induced S and G(2) arrest in multiple tumor cell lines. Biomarkers of CHK1 (pS296 CHK1) activity and cell-cycle inactivity (pY15 CDK1) were induced by genotoxics and inhibited by CCT244747 both in vitro and in vivo, producing enhanced DNA damage and apoptosis. Active tumor concentrations of CCT244747 were obtained following oral administration. The antitumor activity of both gemcitabine and irinotecan were significantly enhanced by CCT244747 in several human tumor xenografts, giving concomitant biomarker modulation indicative of CHK1 inhibition. CCT244747 also showed marked antitumor activity as a single agent in a MYCN-driven neuroblastoma. CONCLUSION: CCT244747 represents the first structural disclosure of a highly selective, orally active CHK1 inhibitor and warrants further evaluation alone or combined with genotoxic anticancer therapies.


Assuntos
Aminopiridinas/administração & dosagem , Neoplasias Experimentais , Neuroblastoma , Proteínas Quinases , Pirimidinas/administração & dosagem , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Quinases/genética , Proteínas Quinases/metabolismo
5.
J Med Chem ; 54(24): 8328-42, 2011 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-22111927

RESUMO

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.


Assuntos
Antineoplásicos/síntese química , Isoquinolinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/metabolismo , Pirazinas/síntese química , Piridinas/síntese química , Trifosfato de Adenosina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Camundongos , Camundongos Nus , Conformação Molecular , Transplante de Neoplasias , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo
6.
Bioorg Med Chem Lett ; 20(14): 4045-9, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20561787

RESUMO

A range of 3,6-di(hetero)arylimidazo[1,2-a]pyrazine ATP-competitive inhibitors of CHK1 were developed by scaffold hopping from a weakly active screening hit. Efficient synthetic routes for parallel synthesis were developed to prepare analogues with improved potency and ligand efficiency against CHK1. Kinase profiling showed that the imidazo[1,2-a]pyrazines could inhibit other kinases, including CHK2 and ABL, with equivalent or better potency depending on the pendant substitution. These 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines appear to represent a general kinase inhibitor scaffold.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos
7.
Mol Cancer Ther ; 9(1): 89-100, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20053762

RESUMO

Genotoxic antitumor agents continue to be the mainstay of current cancer chemotherapy. These drugs cause DNA damage and activate numerous cell cycle checkpoints facilitating DNA repair and the maintenance of genomic integrity. Most human tumors lack functional p53 and consequently have compromised G(1)-S checkpoint control. This has led to the hypothesis that S and G(2)-M checkpoint abrogation may selectively enhance genotoxic cell killing in a p53-deficient background, as normal cells would be rescued at the G(1)-S checkpoint. CHK1 is a serine/threonine kinase associated with DNA damage-linked S and G(2)-M checkpoint control. SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC(50) of 13.3 nmol/L on the isolated human enzyme. This compound abrogates an etoposide-induced G(2) arrest with an IC(50) of 55 nmol/L in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0- to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion. Biomarker studies have shown that SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion both in vitro and in vivo. Cytotoxic drug combinations were associated with increased gammaH2AX and poly ADP ribose polymerase cleavage consistent with the SAR-020106-enhanced DNA damage and tumor cell death. Irinotecan and gemcitabine antitumor activity was enhanced by SAR-020106 in vivo with minimal toxicity. SAR-020106 represents a novel class of CHK1 inhibitors that can enhance antitumor activity with selected anticancer drugs in vivo and may therefore have clinical utility.


Assuntos
Isoquinolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Pirazinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Dano ao DNA , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Fase G2/efeitos dos fármacos , Humanos , Irinotecano , Isoquinolinas/administração & dosagem , Isoquinolinas/química , Isoquinolinas/farmacocinética , Camundongos , Camundongos Nus , Mutagênicos/toxicidade , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/química , Pirazinas/farmacocinética , Gencitabina
8.
Comb Chem High Throughput Screen ; 9(7): 545-58, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16925514

RESUMO

The development of structure-activity relationships (SARs) relating to the function of a biological protein is often a long and protracted undertaking when using an iterative medicinal chemistry approach. High throughput screening of ECLiPS (Encoded Combinatorial Libraries on Polymeric Support) libraries can be used to simplify this process. In this paper, we illustrate how a large ECLiPS library of 26,908 compounds, based on a tricyclic core structure, was used to define a multitude of SARs for the oncogenic target, farnesyltransferase (FTase). This library, FT-2, was prepared using a split-and-pool approach in which small molecules are constructed on resin that contains tag/linker constructs to track the synthetic process [1-5] Highly defined SARs were produced from this screen that enhanced our understanding of FTase binding site interactions. The pivotal compounds culled from this library were potent in both cell-free and cell-based FTase assays, selective over the closely related enzyme, geranylgeranyltransferase I (GGTase I), and inhibited the adherent-independent growth of a transformed cell line.


Assuntos
Técnicas de Química Combinatória , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Alquil e Aril Transferases/antagonistas & inibidores , Sítios de Ligação , Bioensaio , Técnicas de Cultura de Células , Linhagem Celular Transformada/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas/efeitos dos fármacos
9.
Bioorg Med Chem Lett ; 16(3): 507-11, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16289818

RESUMO

Farnesyltransferase inhibitors identified from an ECLiPS library were optimized using solution-phase synthesis. X-ray crystallography of inhibited complexes was used to identify substructures that coordinate to the active site zinc. The X-ray structures were ultimately used to guide the design of second-generation analogs with FTase IC(50)s of less than 1.0 nM.


Assuntos
Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Biblioteca de Peptídeos , Zinco/química , Animais , Sítios de Ligação , Catálise , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Farnesiltranstransferase/síntese química , Concentração Inibidora 50 , Camundongos , Células NIH 3T3 , Relação Estrutura-Atividade
10.
Org Lett ; 7(24): 5433-6, 2005 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-16288524

RESUMO

[reaction: see text] A practical and general two-step synthesis of carbamate-protected (E)-vinylglycines from aliphatic aldehydes is reported. The key step involves the kinetic alpha-protonation of dianionic dienolates derived from dehydroamino acids.


Assuntos
Aminoácidos/química , Glicina/análogos & derivados , Catálise , Glicina/síntese química , Glicina/química , Indicadores e Reagentes , Estrutura Molecular , Estereoisomerismo
11.
Bioorg Med Chem Lett ; 15(24): 5537-43, 2005 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16202593

RESUMO

In order to fully explore structure-activity relationships at the 1- and 2-positions of the piperazine core of tricyclic farnesyltransferase inhibitors, an 11,718-member ECLiPS library was synthesized and screened in a farnesyltransferase scintillation proximity assay. A detailed description of the library and analyses of the screening data will be provided.


Assuntos
Inibidores Enzimáticos/química , Farnesiltranstransferase/antagonistas & inibidores , Piperazinas/química , Piperazinas/farmacologia , Inibidores Enzimáticos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Cinética , Relação Estrutura-Atividade
12.
Curr Top Med Chem ; 4(7): 671-86, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15032681

RESUMO

The implementation of appropriate automation can make a significant improvement in productivity at each stage of the drug discovery process, if it is incorporated into an efficient overall process. Automated chemistry has evolved rapidly from the 'combinatorial' techniques implemented in many industrial laboratories in the early 1990's which focused primarily on the hit discovery phase, and were highly dependent on solid-phase techniques and instrumentation derived from peptide synthesis. Automated tools and strategies have been developed which can impact the hit discovery, hit expansion and lead optimization phases, not only in synthesis, but also in reaction optimization, work-up, and purification of compounds. This article discusses the implementation of some of these techniques, based especially on experiences at Millennium Pharmaceuticals Research and Development Ltd.


Assuntos
Automação/métodos , Desenho de Fármacos , Tecnologia Farmacêutica/instrumentação , Automação/instrumentação , Desenho de Equipamento , Robótica
13.
J Comb Chem ; 4(1): 23-32, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11831879

RESUMO

A library of 422 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides was prepared in five steps using solution-phase chemistry. The first step in the synthesis was the reaction of ethyl 2-ethoxymethylene-3-oxo-4,4,4-trifluorobutanoate with thiosemicarbazide, which is reported in the literature to afford a 1:1 mixture of ethyl 1-thiocarbamoyl-5-(trifluoromethyl)pyrazole-4-carboxylate and ethyl 1-thiocarbamoyl-3-(trifluoromethyl)pyrazole-4-carboxylate. We reassigned the structure of the product to be a single compound, ethyl 5-hydroxy-1-thiocarbamoyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate. This common intermediate was diversified by reaction with 17 alpha-bromoketones affording, in two steps, 17 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxylic acids. Scavenger resins were used to facilitate formation and purification of up to 27 amides from each of these acids in the last step. In addition, the Curtius reaction was applied to 12 of the acids followed by quenching with alcohols to afford a 108-member carbamate library. Certain compounds in the two libraries were toxic to C. elegans.


Assuntos
Amidas/síntese química , Técnicas de Química Combinatória/métodos , Desenho de Fármacos , Hidrocarbonetos Fluorados/química , Pirazóis/síntese química , Tiazóis/síntese química , Amidas/farmacologia , Animais , Antinematódeos/síntese química , Antinematódeos/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Carbamatos/química , Carbamatos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Nematoides/efeitos dos fármacos , Pirazóis/farmacologia , Tiazóis/farmacologia
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