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1.
Bioorg Med Chem Lett ; 35: 127778, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33422603

RESUMO

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.

2.
Bioorg Med Chem Lett ; 30(12): 127204, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32334911

RESUMO

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

3.
ACS Med Chem Lett ; 9(11): 1117-1122, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30429955

RESUMO

The multifunctional cytokine TGFß plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFß signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFß receptor kinase inhibitors with excellent selectivity for TGFß receptor 1 kinase. The combination of compound 3f and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model.

4.
Bioorg Med Chem ; 26(5): 1026-1034, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29422332

RESUMO

The TGFß-TGFßR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFßR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFßRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFß-stimulated phospho-SMAD was observed in primary human T cells.


Assuntos
Compostos Bicíclicos com Pontes/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Sítios de Ligação , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Células Cultivadas , Cristalografia por Raios X , Desenho de Fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Fosforilação , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases/metabolismo , Pirróis/síntese química , Pirróis/química , Pirróis/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteínas Smad/metabolismo , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/metabolismo , Tiazinas/síntese química , Tiazinas/química , Tiazinas/metabolismo
5.
Bioorg Med Chem Lett ; 21(2): 781-5, 2011 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-21177105
6.
J Med Chem ; 52(21): 6527-30, 2009 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-19821562

RESUMO

Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.


Assuntos
Antineoplásicos/síntese química , Carbamatos/síntese química , Receptores ErbB/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Triazinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Carbamatos/farmacocinética , Carbamatos/farmacologia , Linhagem Celular Tumoral , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Macaca fascicularis , Camundongos , Transplante de Neoplasias , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo , Triazinas/farmacocinética , Triazinas/farmacologia
7.
Bioorg Med Chem Lett ; 18(2): 634-9, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18055203

RESUMO

2-Amino-5-(thioaryl)thiazoles are potent inhibitors of TrkA (e.g., 20h, TrkA IC(50)=0.6 nM) that show anti-proliferative effect in cellular assays. A proposed inhibitor binding mode to TrkA active site is consistent with key SAR observations.


Assuntos
Receptor trkA/antagonistas & inibidores , Tiazóis/farmacologia , Fosforilação , Receptor trkA/metabolismo , Relação Estrutura-Atividade , Tiazóis/química
8.
Bioorg Med Chem Lett ; 17(17): 4947-54, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17606372

RESUMO

Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.


Assuntos
Química Farmacêutica/métodos , Receptores ErbB/química , Neoplasias/tratamento farmacológico , Piperidinas/síntese química , Pirróis/síntese química , Receptor ErbB-2/química , Triazinas/síntese química , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Insetos , Modelos Químicos , Transplante de Neoplasias , Piperidinas/química , Piperidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Triazinas/química , Triazinas/farmacologia
10.
Clin Cancer Res ; 12(20 Pt 1): 6186-93, 2006 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17062696

RESUMO

PURPOSE: The studies described here are intended to characterize the ability of BMS-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (HER) kinase family, to modulate signaling and growth of tumor cells that depend on HER1 and/or HER2. EXPERIMENTAL DESIGN: The potency and selectivity of BMS-599626 were assessed in biochemical assays using recombinant protein kinases, as well as in cell proliferation assays using tumor cell lines with varying degrees of dependence on HER1 or HER2 signaling. Modulation of receptor signaling was determined in cell assays by Western blot analyses of receptor autophosphorylation and downstream signaling. The ability of BMS-599626 to inhibit receptor heterodimer signaling in tumor cells was studied by receptor coimmunoprecipitation. Antitumor activity of BMS-599626 was evaluated using a number of different xenograft models that represent a spectrum of human tumors with HER1 or HER2 overexpression. RESULTS: BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. Biochemical studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 micromol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity. CONCLUSIONS: BMS-599626 is a highly selective and potent inhibitor of HER1 and HER2 kinases and inhibits tumor cell proliferation through modulation of receptor signaling. BMS-599626 inhibits HER1/HER2 receptor heterodimerization and provides an additional mechanism of inhibiting tumors in which receptor coexpression and heterodimerization play a major role in driving tumor growth. The preclinical data support the advancement of BMS-599626 into clinical development for the treatment of cancer.


Assuntos
Antineoplásicos/toxicidade , Inibidores Enzimáticos/toxicidade , Receptores ErbB/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Anticorpos Monoclonais/farmacologia , Antígenos CD8/imunologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Dimerização , Humanos
11.
Mol Cancer Ther ; 5(6): 1571-6, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16818516

RESUMO

Receptor tyrosine kinases (RTK) remain an area of therapeutic interest because of their role in epithelial tumors, and experimental models specific to these targets are highly desirable. Chimeric receptors were prepared by in-frame fusion of the CD8 extracellular sequence with the cytoplasmic sequences of RTKs. A CD8HER2 fusion protein was shown to form disulfide-mediated homodimers and to transform fibroblasts and epithelial cells. CD8RTK fusion proteins transform rat kidney epithelial cells and impart phenotypes that may reflect signaling specificity inherent in the native receptors. Transgenic expression of CD8HER2 and CD8Met in mice resulted in the formation of salivary and mammary gland tumors. The transgenic tumors allow the derivation of allograft tumors and cell lines that are sensitive to inhibition by small molecule kinase inhibitors. This approach provides excellent cell and tumor models for the characterization of signaling properties of diverse RTKs and for the evaluation of rationally designed antagonists targeting these kinases.


Assuntos
Antígenos CD8/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias Mamárias Animais/genética , Receptor ErbB-2/metabolismo , Proteínas Recombinantes de Fusão/genética , Neoplasias das Glândulas Salivares/genética , Animais , Western Blotting , Transformação Celular Neoplásica/genética , Dimerização , Modelos Animais de Doenças , Dissulfetos/farmacologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos Transgênicos , Fragmentos de Peptídeos/imunologia , Plasmídeos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Ratos , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias das Glândulas Salivares/tratamento farmacológico , Neoplasias das Glândulas Salivares/etiologia , Transfecção
13.
Bioorg Med Chem Lett ; 15(21): 4774-9, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16111887

RESUMO

A novel series of dual EGFR and HER2 inhibitors based on the pyrrolo[2,1-f][1,2,4]triazine nucleus is described. A general route toward their synthesis, which enables functionalization at multiple sites, has been developed. Biological evaluation in enzymatic and cell-based assays has identified a series of C-6 carbamates with potent biochemical and cellular activities.


Assuntos
Receptores ErbB/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Sítios de Ligação , Carbamatos/síntese química , Carbamatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Modelos Moleculares , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacologia
14.
Prostate ; 65(2): 159-70, 2005 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-15924334

RESUMO

BACKGROUND: Endocrine therapy of prostate cancer (PCa) relies on agents which disrupt the biosynthesis of testosterone in the testis and/or by direct antagonism of active hormone on the androgen receptor (AR) in non-gonadal target tissues of hormone action such as the prostate. METHODS: In an effort to evaluate new therapies which could inhibit gonadal or non-gonadal testosterone biosynthesis, we developed high throughput biochemical and cellular screening assays to identify inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3), the enzyme catalyzing the conversion of androstenedione (AdT) to testosterone. RESULTS: Initial screening efforts identified a natural product, 18beta-glycyrrhetinic acid, and a novel derivative of AdT, 3-O-benzylandrosterone, as potent inhibitors of the enzyme. Further efforts led to the identification of several classes of non-steroidal, low molecular weight compounds that potently inhibited 17beta-HSD3 enzymatic activity. One of the most potent classes of 17beta-HSD3 inhibitors was a series of anthranilamide small molecules identified from a collection of compounds related to non-steroidal modulators of nuclear hormone receptors. The anthranilamide based 17beta-HSD3 inhibitors were exemplified by BMS-856, a compound displaying low nanomolar inhibition of 17beta-HSD3 enzymatic activity. In addition, this series of compounds displayed potent inhibition of 17beta-HSD3-mediated cellular conversion of AdT to testosterone and inhibited the 17beta-HSD3-mediated conversion of testosterone necessary to promote AR-dependent transcription. CONCLUSIONS: The identification of non-steroidal functional inhibitors of 17beta-HSD3 may be a useful complementary approach for the disruption of testosterone biosynthesis in the treatment of PCa.


Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 17-Hidroxiesteroide Desidrogenases/fisiologia , Anti-Inflamatórios/farmacologia , Ácido Glicirretínico/farmacologia , Testosterona/biossíntese , ortoaminobenzoatos/farmacologia , Androstenodiona/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico
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