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1.
Bioorg Med Chem Lett ; 22(5): 1850-3, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22326395

RESUMO

The vast majority of cancer patients die from metastasis, the process by which cancer cells spread to secondary tissues through body fluids. Peritoneal carcinomatosis is a type of metastasis in which cancer cells gain access to the intra-abdominal cavity and then implant in the peritoneum, the thin tissue that lines the abdominal wall and internal organs. Unfortunately, peritoneal carcinomatosis can occur following surgical resection of intra-abdominal malignancies. We previously reported proapoptotic activity of (2E)-3-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-2-propenenitrile (BAY 11-7085, 1) on colon and pancreatic cancer cells during adhesion and demonstrated that this compound could significantly inhibit peritoneal carcinomatosis in mice.(1,2) In order to determine the chemical basis of the anti-metastatic properties of BAY 11-7085, a series of analogs were synthesized and evaluated for their ability to induce apoptosis in pancreatic and ovarian cancer cells during adhesion to mesothelial cells, which line the surface of the peritoneum. The co-culture assay results were validated using a murine peritoneal carcinomatosis model. These analogs may greatly benefit patients undergoing surgical resections of colorectal, pancreatic, and ovarian cancers depending on their tolerability.


Assuntos
Acrilonitrila/química , Acrilonitrila/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Acrilonitrila/síntese química , Animais , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Carcinoma/patologia , Carcinoma/secundário , Linhagem Celular Tumoral , Técnicas de Cocultura , Feminino , Humanos , Camundongos , Nitrilas/síntese química , Nitrilas/química , Nitrilas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Ovário/efeitos dos fármacos , Ovário/patologia , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/secundário , Peritônio/efeitos dos fármacos , Peritônio/patologia , Sulfonas/síntese química , Sulfonas/química , Sulfonas/uso terapêutico
3.
Bioorg Med Chem Lett ; 21(13): 3877-80, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21632243
4.
Bioorg Med Chem Lett ; 21(1): 164-7, 2011 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21123062

RESUMO

The HGF-c-Met signaling axis is an important paracrine mediator of epithelial-mesenchymal cell interactions involving the regulation of multiple cellular activities including cell motility, mitogenesis, morphogenesis, and angiogenesis. Dysregulation of c-Met signaling (e.g., overexpression or increased activation) is associated with the development of a wide range of tumor types; thus, inhibiting the HGF-c-Met pathway is predicted to lead to anti-tumor effects in many cancers. Elaboration of a 2-arylaminopyrimidine scaffold led to a series of potent c-Met inhibitors bearing a C4-2-amino-N-methylbenzamide group. Specifically, a series of C2-benzazepinone analogs demonstrated potent inhibition of c-Met in enzymatic and cellular assays. Kinase selectivity could be tuned by varying the nature of the alkyl group on the benzazepinone nitrogen.


Assuntos
Compostos Bicíclicos com Pontes/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirimidinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Humanos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 21(2): 660-3, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21190849

RESUMO

Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model. Subsequent PK/PD studies suggested that a metabolite contributed to the overall in vivo response.


Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/uso terapêutico , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Humanos , Camundongos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Med Chem ; 64(15): 11302-11329, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34292726

RESUMO

Indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential immunotherapeutic target in oncology. We developed a class of inhibitors with a conformationally constrained bicyclo[3.1.0]hexane core. These potently inhibited IDO1 in a cellular context by binding to the apoenzyme, as elucidated by biochemical characterization and X-ray crystallography. A SKOV3 tumor model was instrumental in differentiating compounds, leading to the identification of IACS-9779 (62) and IACS-70465 (71). IACS-70465 has excellent cellular potency, a robust pharmacodynamic response, and in a human whole blood assay was more potent than linrodostat (BMS-986205). IACS-9779 with a predicted human efficacious once daily dose below 1 mg/kg to sustain >90% inhibition of IDO1 displayed an acceptable safety margin in rodent toxicology and dog cardiovascular studies to support advancement into preclinical safety evaluation for human development.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
7.
Bioorg Med Chem ; 18(12): 4351-62, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20483621

RESUMO

Dysregulation of the anaplastic lymphoma kinase (ALK) is implicated in a variety of cancers. A series of tetrahydropyrido[2,3-b]pyrazines was constructed as ring-constrained analogs of a known aminopyridine kinase scaffold. Chemistry was developed to rapidly elaborate the SAR, structural elements impacting ALK inhibitory activity were exploited, and kinase selective analogs were identified that inhibit ALK with IC(50) values approximately 10 nM (enzyme) and approximately 150 nM (cell).


Assuntos
Antineoplásicos/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazinas/química , Quinase do Linfoma Anaplásico , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Simulação por Computador , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Pirazinas/síntese química , Pirazinas/farmacologia , Receptores Proteína Tirosina Quinases , Relação Estrutura-Atividade
8.
J Med Chem ; 63(21): 12957-12977, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33118821

RESUMO

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.


Assuntos
Inibidores Enzimáticos/química , Glutaminase/antagonistas & inibidores , Triazóis/farmacocinética , Administração Oral , Animais , Linhagem Celular Tumoral , Cães , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Glutaminase/genética , Glutaminase/metabolismo , Meia-Vida , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Microssomos/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Relação Estrutura-Atividade , Triazóis/química , Triazóis/metabolismo
9.
Bioorg Med Chem Lett ; 18(2): 749-54, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18054227

RESUMO

Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa) inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido linker between the pyrazole and proximal phenyl moiety of the razaxaban scaffold was replaced with a methylene group. The resulting ketones demonstrated excellent potency and selectivity for fXa but initially had poor oral bioavailability. Optimization by conversion from a P1 aminobenzisoxazole to a P1 p-methoxyphenyl residue, replacing the 3-trifluoromethylpyrazole with a 3-amidopyrazole, and employing a pyridone P4 group provided a fXa inhibitor with a potency and pharmacokinetic profile equivalent to that of razaxaban and improved selectivity over thrombin.


Assuntos
Inibidores do Fator Xa , Pirazóis/química , Pirazóis/farmacologia , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Animais , Células CACO-2 , Cães , Humanos , Pirazóis/farmacocinética , Inibidores de Serina Proteinase/farmacocinética , Relação Estrutura-Atividade
10.
J Med Chem ; 59(4): 1440-54, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-26061247

RESUMO

The bromodomain containing proteins TRIM24 (tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethylbenzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM and ITC Kd = 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Benzimidazóis/química , Benzimidazóis/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Desenho de Fármacos , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Animais , Benzimidazóis/farmacocinética , Proteínas de Transporte/química , Proteínas de Ligação a DNA , Feminino , Humanos , Metilação , Camundongos , Simulação de Acoplamento Molecular , Proteínas Nucleares/química , Ligação Proteica
11.
J Med Chem ; 58(3): 1140-58, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25581261

RESUMO

The spread of intra-abdominal cancers is a vexing clinical problem for which there is no widely effective treatment. We discovered previously that (2E)-3-[(4-tert-butylphenyl)sulfonyl]acrylonitrile (1) induced cancer cell apoptosis during adhesion to normal mesothelial cells which line the peritoneum. We recently demonstrated that the sulfonylacrylonitrile portion of 1 and hydrophobic aryl substitution were essential for pro-apoptotic activity in cancer cells. Here we synthesized a diverse series of analogues of 1 in order to improve the efficacy and pharmaceutical properties. Analogues and 1 were compared in their ability to cause cancer cell death during adhesion to normal mesothelial cell monolayers. Potent analogues identified in the in vitro assay were validated and found to exhibit improved inhibition of intra-abdominal cancer in two clinically relevant murine models of ovarian and pancreatic cancer spread and metastasis, highlighting their potential clinical use as an adjunct to surgical resection of cancers.


Assuntos
Acrilonitrila/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Sulfonas/farmacologia , Acrilonitrila/síntese química , Acrilonitrila/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Células HT29 , Humanos , Camundongos , Estrutura Molecular , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/secundário , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/secundário , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química
12.
Assay Drug Dev Technol ; 10(4): 375-81, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22428803

RESUMO

Heat shock protein-90 (HSP90) is an ATP-dependent molecular chaperone with intrinsic ATPase activity. HSP90 is required for the stability and function of client proteins, many of which are involved in oncogenesis. Thus, identification of HSP90 inhibitors would potentially lead to the discovery of cancer therapeutics. Here, we present a high-throughput screening campaign utilizing two geldanamycin (GM)-labeled probes in a fluorescence polarization (FP) assay. For the primary screen, a previously reported green BODIPY-labeled GM (GM-BODIPY) was used to evaluate a library collection of about 400,000 compounds. From this screen, 3058 compounds showed >30% inhibition. To distinguish true positives from compound interference, a confirmatory screen was deemed necessary. Accordingly, a red-shifted FP binding assay was developed using GM labeled with red BODIPY. This tool enabled reliable identification of promising HSP90α inhibitors.


Assuntos
Polarização de Fluorescência/métodos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Benzoquinonas/farmacologia , Compostos de Boro/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , DNA Complementar/genética , Avaliação Pré-Clínica de Medicamentos , Corantes Fluorescentes , Expressão Gênica , Proteínas de Choque Térmico HSP90/biossíntese , Proteínas de Choque Térmico HSP90/genética , Lactamas Macrocíclicas/farmacologia
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