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1.
Mol Cancer Ther ; 22(12): 1465-1478, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37722716

RESUMO

New antibodies-drug conjugate (ADC) payloads overcoming chemoresistance and killing also poorly proliferating tumors at well-tolerated doses are much desired. Duocarmycins are a well-known class of highly potent cytotoxic agents, with DNA minor groove-binding and alkylation properties, active also in chemoresistant tumors. Although different duocarmycin derivatives have been used during the years as payloads for ADC production, unfavorable physicochemical properties impaired the production of ADCs with optimal features. Optimization of the toxin to balance reactivity and stability features and best linker selection allowed us to develop the novel duocarmycin-like payload-linker NMS-P945 suitable for conjugation to mAbs with reproducible drug-antibody ratio (DAR) >3.5. When conjugated to trastuzumab, it generated an ADC with good internalization properties, ability to induce bystander effect and immunogenic cell death. Moreover, it showed strong target-driven activity in cells and cytotoxic activity superior to trastuzumab deruxtecan tested, in parallel, in cell lines with HER2 expression. High in vivo efficacy with cured mice at well-tolerated doses in HER2-driven models was also observed. A developed pharmacokinetic/pharmacodynamic (PK/PD) model based on efficacy in mice and cynomolgus monkey PK data, predicted tumor regression in patients upon administration of 2 doses of trastuzumab-NMS-P945-ADC at 0.5 mg/kg. Thus, considering the superior physicochemical features for ADC production and preclinical results obtained with the model trastuzumab ADC, including bystander effect, immunogenic cell death and activity in chemoresistant tumors, NMS-P945 represents a highly effective, innovative payload for the creation of novel, next-generation ADCs.


Assuntos
Antineoplásicos , Imunoconjugados , Humanos , Camundongos , Animais , Duocarmicinas , Macaca fascicularis/metabolismo , Receptor ErbB-2/metabolismo , Linhagem Celular Tumoral , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunoconjugados/química , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Chem Biol ; 4(6): 357-65, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18469809

RESUMO

Cdc7 is an essential kinase that promotes DNA replication by activating origins of replication. Here, we characterized the potent Cdc7 inhibitor PHA-767491 (1) in biochemical and cell-based assays, and we tested its antitumor activity in rodents. We found that the compound blocks DNA synthesis and affects the phosphorylation of the replicative DNA helicase at Cdc7-dependent phosphorylation sites. Unlike current DNA synthesis inhibitors, PHA-767491 prevents the activation of replication origins but does not impede replication fork progression, and it does not trigger a sustained DNA damage response. Treatment with PHA-767491 results in apoptotic cell death in multiple cancer cell types and tumor growth inhibition in preclinical cancer models. To our knowledge, PHA-767491 is the first molecule that directly affects the mechanisms controlling initiation as opposed to elongation in DNA replication, and its activities suggest that Cdc7 kinase inhibition could be a new strategy for the development of anticancer therapeutics.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Replicação do DNA/efeitos dos fármacos , DNA/efeitos dos fármacos , Piperidonas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirróis/farmacologia , Animais , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/biossíntese , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Células HeLa , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Componente 2 do Complexo de Manutenção de Minicromossomo , Estrutura Molecular , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/química , Fosforilação , Piperidonas/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Pirróis/química , Ratos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Med Chem ; 51(3): 487-501, 2008 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-18201066

RESUMO

Cdc7 kinase is an essential protein that promotes DNA replication in eukaryotic organisms. Genetic evidence indicates that Cdc7 inhibition can cause selective tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 small-molecule inhibitors for the treatment of cancers. In this paper, the synthesis and structure-activity relationships of 2-heteroaryl-pyrrolopyridinones, the first potent Cdc7 kinase inhibitors, are described. Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one, progress toward a simple scaffold, tailored for Cdc7 inhibition, is reported.


Assuntos
Antineoplásicos/síntese química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridonas/síntese química , Pirróis/síntese química , Sequência de Aminoácidos , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Proteínas de Ciclo Celular/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica , Proteínas Serina-Treonina Quinases/química , Piridonas/química , Piridonas/farmacologia , Pirróis/química , Pirróis/farmacologia , Homologia de Sequência de Aminoácidos , Relação Estrutura-Atividade
4.
Clin Cancer Res ; 12(9): 2856-61, 2006 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-16675581

RESUMO

The novel indolocarbazole edotecarin (J-107088, formerly ED-749) differs from other topoisomerase I inhibitors both pharmacokinetically and pharmacodynamically. In vitro, it is more potent than camptothecins and has a variable cytotoxic activity in 31 different human cancer cell lines. Edotecarin also possesses greater than additive inhibitory effects on cell proliferation when used in combination with other agents tested in vitro against various cancer cell lines. The present in vivo studies were done to extend the in vitro findings to characterize the antitumor effects of edotecarin when used either alone or in combination with other agents (i.e., 5-fluorouracil, irinotecan, cisplatin, oxaliplatin, and SU11248) in the HCT-116 human colon cancer xenograft model. Treatment effects were based on the delay in onset of an exponential growth of tumors in drug-treated versus vehicle control-treated groups. In all studies, edotecarin was active both as a single agent and in combination with other agents. Combination therapy resulted in greater than additive effects, the extent of which depended on the specific dosage regimen. Toxicity in these experiments was minimal. Of all 359 treated mice, the six that died of toxicity were in the high-dose edotecarin/oxaliplatin group. The results suggest that edotecarin may serve as effective chemotherapy of colon cancer when used as a single agent, in combination with standard regimens and other topoisomerase inhibitors or with novel agents, such as the multitargeted tyrosine kinase inhibitor SU11248.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carbazóis/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Indóis/uso terapêutico , Inibidores da Topoisomerase I , Animais , Carbazóis/administração & dosagem , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Feminino , Humanos , Indóis/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante Heterólogo
5.
Adv Exp Med Biol ; 604: 137-48, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17695726

RESUMO

The discovery of agents which disrupt cancer cell division by specifically targeting key components of the cell-cycle machinery represents a major focus of recent drug discovery efforts in Oncology. The drug discovery process can be greatly enhanced by multiparametric cellular analysis which can assist in confirmation, often in a few multiplexed assays, of the mechanism of action (MOA) of compounds identified through biochemical screening or similar in vitro methods. High-Content Analysis (HCA) is a technique based on automated microscopy which enables multiparametric analysis of fluorescent indicators to define cellular responses to compound treatment. Several distinct fluorescence channels can be acquired and analyzed within a single measure in the same cell population. Here we present a multiparametric HCA approach to characterize potential cell-cycle inhibitors in osteosarcoma U-2 OS adherent cell cultures. This approach allows monitoring of compound-induced cell-cycle perturbations by analyzing specific cellular markers such as nuclear morphology, DNA content or histone H3 phosphorylation. Moreover, the induction of DNA damage response or apoptosis can also be readily evaluated. By considering the profile of the investigated cellular markers at different compound concentrations, a fingerprint defines the cellular and molecular phenotype associated with each compound.


Assuntos
Ciclo Celular/efeitos dos fármacos , Microscopia de Fluorescência/métodos , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Dano ao DNA , DNA Complementar/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Histonas/metabolismo , Humanos , Modelos Biológicos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Fenótipo
6.
Chempluschem ; 78(7): 663-669, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31986630

RESUMO

The introduction of a hydrophobic group at position 7 of 9-fluorenone-2-carboxylic acid generates new tubulin binders, the design of which is suggested by modeling studies. The synthesis is based on the use of 2,7-dibromo-fluorenone as starting material. The antiproliferative activity on two different cell lines, fluorescent microscopy, flow cytometry, and sedimentation assay tests confirmed the supposed mechanism.

7.
Mol Cancer Ther ; 11(4): 1006-16, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22319201

RESUMO

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor prognosis. Although five different PLKs are described in humans, depletion or inhibition of kinase activity of PLK1 is sufficient to induce cell-cycle arrest and apoptosis in cancer cell lines and in xenograft tumor models. NMS-P937 is a novel, orally available PLK1-specific inhibitor. The compound shows high potency in proliferation assays having low nanomolar activity on a large number of cell lines, both from solid and hematologic tumors. NMS-P937 potently causes a mitotic cell-cycle arrest followed by apoptosis in cancer cell lines and inhibits xenograft tumor growth with clear PLK1-related mechanism of action at well-tolerated doses in mice after oral administration. In addition, NMS-P937 shows potential for combination in clinical settings with approved cytotoxic drugs, causing tumor regression in HT29 human colon adenocarcinoma xenografts upon combination with irinotecan and prolonged survival of animals in a disseminated model of acute myelogenous leukemia in combination with cytarabine. NMS-P937, with its favorable pharmacologic parameters, good oral bioavailability in rodent and nonrodent species, and proven antitumor activity in different preclinical models using a variety of dosing regimens, potentially provides a high degree of flexibility in dosing schedules and warrants investigation in clinical settings.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Leucemia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirazóis/farmacologia , Quinazolinas/farmacologia , Administração Oral , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Cães , Feminino , Células HL-60 , Haplorrinos , Humanos , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Camundongos , Camundongos Nus , Camundongos SCID , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto , Quinase 1 Polo-Like
8.
J Med Chem ; 53(9): 3532-51, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-20397705

RESUMO

Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 microM) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC(50) values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.


Assuntos
Antineoplásicos/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Quinazolinas/farmacologia , Trifosfato de Adenosina , Administração Oral , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Mimetismo Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/química , Quinazolinas/uso terapêutico , Relação Estrutura-Atividade , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Quinase 1 Polo-Like
9.
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
10.
J Med Chem ; 52(14): 4380-90, 2009 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-19555113

RESUMO

Cdc7 kinase has recently emerged as an attractive target for cancer therapy and low-molecular-weight inhibitors of Cdc7 kinase have been found to be effective in the inhibition of tumor growth in animal models. In this paper, we describe synthesis and structure-activity relationships of new 1H-pyrrolo[2,3-b]pyridine derivatives identified as inhibitors of Cdc7 kinase. Progress from (Z)-2-phenyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,5-dihydro-4H-imidazol-4-one (1) to [(Z)-2-(benzylamino)-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-1,3-thiazol-4(5H)-one] (42), a potent ATP mimetic inhibitor of Cdc7 kinase with IC(50) value of 7 nM, is also reported.


Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Proteínas de Ciclo Celular/química , Linhagem Celular , Humanos , Modelos Moleculares , Conformação Molecular , Inibidores de Proteínas Quinases/análogos & derivados , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Piridinas/química , Relação Estrutura-Atividade
11.
J Med Chem ; 52(2): 293-307, 2009 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-19115845

RESUMO

Cdc7 kinase is a key regulator of the S-phase of the cell cycle, known to promote the activation of DNA replication origins in eukaryotic organisms. Cdc7 inhibition can cause tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 inhibitors for the treatment of cancer. In this paper, we conclude the structure-activity relationships study of the 2-heteroaryl-pyrrolopyridinone class of compounds that display potent inhibitory activity against Cdc7 kinase. Furthermore, we also describe the discovery of 89S, [(S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoro-ethyl)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one], as a potent ATP mimetic inhibitor of Cdc7. Compound 89S has a Ki value of 0.5 nM, inhibits cell proliferation of different tumor cell lines with an IC50 in the submicromolar range, and exhibits in vivo tumor growth inhibition of 68% in the A2780 xenograft model.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridonas/farmacologia , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Cães , Descoberta de Drogas , Humanos , Espectroscopia de Ressonância Magnética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Piridonas/química , Piridonas/farmacocinética , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , Relação Estrutura-Atividade
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