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1.
ChemMedChem ; 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32003940

RESUMO

LSD1 is a lysine demethylase highly involved in initiation and development of cancer. To design highly effective covalent inhibitors, a strategy is to fill its large catalytic cleft by designing tranylcypromine (TCP) analogs decorated with long, hindered substituents. We prepared three series of TCP analogs, carrying aroyl- and arylacetylamino (1 a-h), Z-amino acylamino (2 a-o), or double-substituted benzamide (3 a-n) residues at the C4 or C3 position of the phenyl ring. Further fragments obtained by chemical manipulation applied on the TCP scaffold (compounds 4 a-i) were also prepared. When tested against LSD1, most of 1 and 3 exhibited IC50 values in the low nanomolar range, with 1 e and 3 a,d,f,g being also the most selective respect to monoamine oxidases. In MV4-11 AML and NB4 APL cells compounds 3 were the most potent, displaying up to sub-micromolar cell growth inhibition against both cell lines (3 a) or against NB4 cells (3 c). The most potent compounds in cellular assays were also able to induce the expression of LSD1 target genes, such as GFI-1b, ITGAM, and KCTD12, as functional read-out for LSD1 inhibition. Mouse and human intrinsic clearance data highlighted the high metabolic stability of compounds 3 a, 3 d and 3 g. Further studies will be performed on the new compounds 3 a and 3 c to assess their anticancer potential in different cancer contexts.

2.
Future Med Chem ; 9(11): 1161-1174, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28722470

RESUMO

BACKGROUND: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor. MATERIAL & METHODS: The KDM1A inhibitors 5a-w were synthesized and tested in vitro and in vivo. The biochemical potency was determined, modulation of target in cells was demonstrated on KDM1A-dependent genes and the anti-clonogenic activity was performed in murine acute promyelocytic Leukemia (APL) blasts. An in vivo efficacy experiment was conducted using an established murine promyelocytic leukemia model. RESULTS: We report a new series of tranylcypromine derivatives substituted on the cyclopropyl moiety, endowed with high potency in both biochemical and cellular assays. CONCLUSION: The most interesting derivative (5a) significantly improved survival rate after oral administration in a murine model of promyelocitic leukemia.


Assuntos
Antineoplásicos/síntese química , Histona Desmetilases/antagonistas & inibidores , Leucemia Promielocítica Aguda/tratamento farmacológico , Tranilcipromina/análogos & derivados , Tranilcipromina/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular , Humanos , Leucemia Promielocítica Aguda/patologia , Camundongos , Relação Estrutura-Atividade , Tranilcipromina/farmacocinética , Tranilcipromina/farmacologia
3.
J Med Chem ; 60(5): 1673-1692, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28186755

RESUMO

Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2.9 µM) in complex with the enzyme. Initial expansion of this chemical class, both modifying core structure and decorating benzamide moiety, was directed toward the definition of the moieties responsible for the interaction with the enzyme. Preliminary optimization led to compound 90, which inhibited the enzyme with a submicromolar IC50 (0.162 µM), capable of inhibiting the target in cells.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Pirróis/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Espectroscopia de Prótons por Ressonância Magnética , Pirróis/química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
4.
J Med Chem ; 60(5): 1693-1715, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28186757

RESUMO

The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.


Assuntos
Inibidores Enzimáticos/farmacologia , Lisina/química , Pirróis/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Drogas , Inibidores Enzimáticos/química , Transferência Ressonante de Energia de Fluorescência , Ensaios de Triagem em Larga Escala , Histona Desmetilases , Humanos , Concentração Inibidora 50 , Pirróis/química , Relação Estrutura-Atividade
5.
J Med Chem ; 59(4): 1501-17, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26702542

RESUMO

We report the stereoselective synthesis and biological activity of a novel series of tranylcypromine (TCPA) derivatives (14a-k, 15, 16), potent inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic potential of acute leukemia cell lines. In particular three molecules (14d, 14e, and 14g) showing selectivity versus MAO A and remarkably inhibiting colony formation in THP-1 human leukemia cells, were assessed in mouse for their preliminary pharmacokinetic. 14d and 14e were further tested in vivo in a murine acute promyelocytic leukemia model, resulting 14d the most effective. Its two enantiomers were synthesized: the (1S,2R) enantiomer 15 showed higher activity than its (1R,2S) analogue 16, in both biochemical and cellular assays. Compound 15 exhibited in vivo efficacy after oral administration, determining a 62% increased survival in mouse leukemia model with evidence of KDM1A inhibition. The biological profile of compound 15 supports its further investigation as a cancer therapeutic.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Histona Desmetilases/antagonistas & inibidores , Leucemia Promielocítica Aguda/tratamento farmacológico , Tranilcipromina/química , Tranilcipromina/uso terapêutico , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Histona Desmetilases/metabolismo , Humanos , Leucemia Promielocítica Aguda/metabolismo , Relação Estrutura-Atividade , Tranilcipromina/administração & dosagem , Tranilcipromina/farmacologia
6.
Eur J Med Chem ; 94: 163-74, 2015 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-25768700

RESUMO

The pure enantiomers of the N-(2-, 3-, and 4-(2-aminocyclopropyl)phenyl)benzamides hydrochlorides 11a-j were prepared and tested against LSD1 and MAO enzymes. The evaluation of the regioisomers 11a-j highlighted a net increase of the anti-LSD1 potency by shifting the benzamide moiety from ortho to meta and mainly to para position of tranylcypromine phenyl ring, independently from their trans or cis stereochemistry. In particular, the para-substituted 11a,b (trans) and 11g,h (cis) compounds displayed LSD1 and MAO-A inhibition at low nanomolar levels, while were less potent against MAO-B. The meta analogs 11c,d (trans) and 11i,j (cis) were in general less potent, but more efficient against MAO-A than against LSD1. In cellular assays, all the para and meta enantiomers were able to inhibit LSD1 by inducing Gfi-1b and ITGAM gene expression, with 11b,c and 11g-i giving the highest effects. Moreover, 11b and 11g,h strongly inhibited the clonogenic potential of murine promyelocytic blasts.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Leucemia/tratamento farmacológico , Leucemia/genética , Tranilcipromina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia/patologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Camundongos , Camundongos Endogâmicos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Tranilcipromina/farmacologia
7.
ACS Med Chem Lett ; 6(2): 173-7, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25699146

RESUMO

The pure four diastereomers (11a-d) of trans-benzyl (1-((4-(2-aminocyclopropyl)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate hydrochloride 11, previously described by us as LSD1 inhibitor, were obtained by enantiospecific synthesis/chiral HPLC separation method. Tested in LSD1 and MAO assays, 11b (S,1S,2R) and 11d (R,1S,2R) were the most potent isomers against LSD1 and were less active against MAO-A and practically inactive against MAO-B. In cells, all the four diastereomers induced Gfi-1b and ITGAM gene expression in NB4 cells, accordingly with their LSD1 inhibition, and 11b and 11d inhibited the colony forming potential in murine promyelocytic blasts.

8.
Eur J Med Chem ; 92: 377-86, 2015 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-25585008

RESUMO

Epigenetics alterations including histone methylation and acetylation, and DNA methylation, are thought to play important roles in the onset and progression of cancer in numerous tumour cell lines. Lysine-specific demethylase 1 (LSD1 or KDM1A) is highly expressed in different cancer types and inhibiting KDM1A activity seems to have high therapeutic potential in cancer treatment. In the recent years, several inhibitors of KDM1A have been prepared and disclosed. The majority of these derivatives were designed based on the structure of tranylcypromine, as the cyclopropane core is responsible for the covalent interaction between the inhibitor and the catalytic domain of KDM proteins. In this study, we have further extended the SAR regarding compounds 1a-e, which were recently found to inhibit KDM1A with good activity. The decoration of the phenyl ring at the ß-position of the cyclopropane ring with small functional groups, mostly halogenated, and in particular at the meta position, led to a significant improvement of the inhibitory activity against KDM1A, as exemplified by compound 44a, which has a potency in the low nanomolar range (31 nM).


Assuntos
Ciclopropanos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Ciclopropanos/síntese química , Ciclopropanos/química , Relação Dose-Resposta a Droga , Histona Desmetilases/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
9.
Eur J Med Chem ; 86: 352-63, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25173853

RESUMO

Histone demethylase KDM1A (also known as LSD1) has become an attractive therapeutic target for the treatment of cancer as well as other disorders such as viral infections. We report on the synthesis of compounds derived from the expansion of tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. These compounds, which are substituted on the cyclopropyl core moiety, were evaluated for their ability to inhibit KDM1A in vitro as well as to function in cells by modulating the expression of Gfi-1b, a well recognized KDM1A target gene. The molecules were all found to covalently inhibit KDM1A and to become increasingly selective against human monoamine oxidases MAO A and MAO B through the introduction of bulkier substituents on the cyclopropylamine ring. Structural and biochemical analysis of selected trans isomers showed that the two stereoisomers are endowed with similar inhibitory activities against KDM1A, but form different covalent adducts with the FAD co-enzyme.


Assuntos
Ciclopropanos/farmacologia , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Monoaminoxidase/metabolismo , Cristalografia por Raios X , Ciclopropanos/síntese química , Ciclopropanos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona Desmetilases/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
10.
Bioorg Med Chem ; 22(17): 4998-5012, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25009002

RESUMO

We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.


Assuntos
Antineoplásicos/farmacologia , Janus Quinase 2/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Janus Quinase 2/metabolismo , Camundongos , Camundongos SCID , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Especificidade por Substrato
11.
12.
Bioorg Med Chem ; 18(19): 7113-20, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20817473

RESUMO

A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure-activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Tiofenos/farmacologia , Animais , Antineoplásicos/química , Aurora Quinases , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Células HL-60 , Humanos , Masculino , Camundongos , Camundongos SCID , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Pirazóis/síntese química , Pirazóis/química , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Transplante Heterólogo
13.
J Med Chem ; 53(20): 7296-315, 2010 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-20873740

RESUMO

Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.


Assuntos
Antineoplásicos/síntese química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/síntese química , Pirróis/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Relação Estrutura-Atividade , Transplante Heterólogo
14.
J Med Chem ; 52(16): 5152-63, 2009 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-19603809

RESUMO

The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.


Assuntos
Antineoplásicos/síntese química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Pirazóis/síntese química , Quinazolinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Pirazóis/farmacocinética , Pirazóis/farmacologia , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Solubilidade , Relação Estrutura-Atividade , Transplante Heterólogo
16.
Mol Cancer Ther ; 6(12 Pt 1): 3158-68, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18089710

RESUMO

PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition-related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status-dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser(10) is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers.


Assuntos
Benzamidas/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Animais , Aurora Quinase B , Aurora Quinases , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Neoplasias/enzimologia , Fosforilação , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley
17.
J Med Chem ; 49(24): 7247-51, 2006 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-17125279

RESUMO

The optimization of a series of 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition of Aurora kinases led to the identification of compound 9d. This is a potent inhibitor of Aurora kinases that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in vivo tumor models, compound 9d was ultimately selected for further development.


Assuntos
Antineoplásicos/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/síntese química , Pirróis/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Masculino , Camundongos , Modelos Moleculares , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Solubilidade , Relação Estrutura-Atividade
18.
Clin Cancer Res ; 12(13): 4080-9, 2006 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-16818708

RESUMO

PURPOSE: Aurora kinases play critical roles during mitosis in chromosome segregation and cell division. The aim of this study was to determine the preclinical profile of a novel, highly selective Aurora kinase inhibitor, PHA-680632, as a candidate for anticancer therapy. EXPERIMENTAL DESIGN: The activity of PHA-680632 was assayed in a biochemical ATP competitive kinase assay. A wide panel of cell lines was evaluated for antiproliferative activity. Cell cycle analysis. Immunohistochemistry, Western blotting, and Array Scan were used to follow mechanism of action and biomarker modulation. Specific knockdown of the targets by small interfering RNA was followed to validate the observed phenotypes. Efficacy was determined in different xenograft models and in a transgenic animal model of breast cancer. RESULTS: PHA-680632 is active on a wide range of cancer cell lines and shows significant tumor growth inhibition in different animal tumor models at well-tolerated doses. The mechanism of action of PHA-680632 is in agreement with inhibition of Aurora kinases. Histone H3 phosphorylation in Ser10 is mediated by Aurora B kinase, and our kinetic studies on its inhibition by PHA-680632 in vitro and in vivo show that phosphorylation of histone H3 is a good biomarker to follow activity of PHA-680632. CONCLUSIONS: PHA-680632 is the first representative of a new class of Aurora inhibitors with a high potential for further development as an anticancer therapeutic. On treatment, different cell lines respond differentially, suggesting the absence of critical cell cycle checkpoints that could be the basis for a favorable therapeutic window.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Pirróis/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Aurora Quinase B , Aurora Quinases , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Células HL-60 , Células HeLa , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Fenótipo , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos
19.
Bioorg Med Chem Lett ; 16(4): 1084-90, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16290148

RESUMO

We have recently reported about a new class of Aurora-A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. Here we describe the synthesis and early expansion of CDK2/cyclin A-E inhibitors belonging to the same chemical class. Synthesis of the compounds was accomplished using a solution-phase protocol amenable to rapid parallel expansion. Compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit CDK2-mediated tumor cell proliferation have been obtained.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Antineoplásicos/classificação , Aurora Quinases , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Ciclina A/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/classificação , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/síntese química , Relação Estrutura-Atividade
20.
J Med Chem ; 48(8): 3080-4, 2005 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-15828847

RESUMO

Potent and selective Aurora kinase inhibitors were identified from the combinatorial expansion of the 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole bi-cycle, a novel and versatile scaffold designed to target the ATP pocket of protein kinases. The most potent compound reported in this study had an IC(50) of 0.027 microM in the enzymatic assay for Aur-A inhibition and IC(50)s between 0.05 microM and 0.5 microM for the inhibition of proliferation of different tumor cell lines.


Assuntos
Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Piperazinas/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirróis/síntese química , Trifosfato de Adenosina/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinases , Sítios de Ligação , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Combinatória , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Pirróis/química , Pirróis/farmacologia , Relação Estrutura-Atividade
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