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1.
Cancer Res ; 79(8): 1996-2008, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30723115

RESUMO

Expression of the TAM (TYRO3, AXL, MER) family of receptor tyrosine kinases (RTK) has been associated with cancer progression, metastasis, and drug resistance. In immune cells, TAM RTKs can dampen inflammation in favor of homeostatic wound-healing responses, thus potentially contributing to the evasion of cancer cells from immune surveillance. Here we characterize the small-molecule RXDX-106 as a selective and potent pan-TAM RTK inhibitor with slow dissociation kinetics and significant antitumor activity in multiple syngeneic tumor models. Expression of AXL and MER on both immune and tumor cells increased during tumor progression. Tumor growth inhibition (TGI) following treatment with RXDX-106 was observed in wild-type mice and was abrogated in immunodeficient mice, suggesting that the antitumor activity of RXDX-106 is, in part, due to the presence of immune cells. RXDX-106-mediated TGI was associated with increased tumor-infiltrating leukocytes, M1-polarized intratumoral macrophages, and activation of natural killer cells. RXDX-106 proportionally increased intratumoral CD8+ T cells and T-cell function as indicated by both IFNγ production and LCK phosphorylation (pY393). RXDX-106 exhibited its effects via direct actions on TAM RTKs expressed on intratumoral macrophages and dendritic cells, leading to indirect activation of other immune cells in the tumor. RXDX-106 also potentiated the effects of an immune checkpoint inhibitor, α-PD-1 Ab, resulting in enhanced antitumor efficacy and survival. Collectively, these results demonstrate the capacity of RXDX-106 to inhibit tumor growth and progression and suggest it may serve as an effective therapy against multiple tumor types. SIGNIFICANCE: The pan-TAM small-molecule kinase inhibitor RXDX-106 activates both innate and adaptive immunity to inhibit tumor growth and progression, indicating its clinical potential to treat a wide variety of cancers.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/farmacologia , Quinolinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , c-Mer Tirosina Quinase/antagonistas & inibidores , Imunidade Adaptativa , Animais , Apoptose , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Neoplasias do Colo/patologia , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nat Cell Biol ; 20(3): 272-284, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29459781

RESUMO

For cancer cells to survive during extracellular matrix (ECM) detachment, they must inhibit anoikis and rectify metabolic deficiencies that cause non-apoptotic cell death. Previous studies in ECM-detached cells have linked non-apoptotic cell death to reactive oxygen species (ROS) generation, although the mechanistic underpinnings of this link remain poorly defined. Here, we uncover a role for receptor-interacting protein kinase 1 (RIPK1) in the modulation of ROS and cell viability during ECM detachment. We find that RIPK1 activation during ECM detachment results in mitophagy induction through a mechanism dependent on the mitochondrial phosphatase PGAM5. As a consequence of mitophagy, ECM-detached cells experience diminished NADPH production in the mitochondria, and the subsequent elevation in ROS levels leads to non-apoptotic death. Furthermore, we find that antagonizing RIPK1/PGAM5 enhances tumour formation in vivo. Thus, RIPK1-mediated induction of mitophagy may be an efficacious target for therapeutics aimed at eliminating ECM-detached cancer cells.


Assuntos
Células Epiteliais/enzimologia , Matriz Extracelular/metabolismo , Glândulas Mamárias Humanas/enzimologia , Mitocôndrias/enzimologia , Mitofagia , Neoplasias/enzimologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Adesão Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Células Epiteliais/patologia , Matriz Extracelular/patologia , Feminino , Células HCT116 , Células HeLa , Humanos , Glândulas Mamárias Humanas/patologia , Camundongos Nus , Mitocôndrias/patologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , NADP/metabolismo , Metástase Neoplásica , Neoplasias/genética , Neoplasias/patologia , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de Sinais , Carga Tumoral
3.
Mol Cancer Ther ; 17(2): 455-463, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29237803

RESUMO

Activation of tropomyosin receptor kinase (TRK) family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent, and selective kinase inhibitor against TRKA/B/C, ROS1, and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion-driven hematologic malignancies. In acute myelogenous leukemia (AML) cell lines with endogenous expression of the ETV6-NTRK3 fusion gene, entrectinib treatment blocked cell proliferation and induced apoptotic cell death in vitro with subnanomolar IC50 values. Phosphorylation of the ETV6-TRKC fusion protein and its downstream signaling effectors was inhibited by entrectinib treatment in a dose-dependent manner. In animal models, entrectinib treatment at clinically relevant doses resulted in tumor regression that was accompanied by elimination of residual cancer cells from the bone marrow. Our preclinical data demonstrate the potential of entrectinib as an effective treatment for patients with TRK fusion-driven AML and other hematologic malignancies. Mol Cancer Ther; 17(2); 455-63. ©2017 AACR.


Assuntos
Benzamidas/uso terapêutico , Indazóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Animais , Benzamidas/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Indazóis/farmacologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos SCID , Inibidores de Proteínas Quinases/farmacologia , Peixe-Zebra
4.
Issues Law Med ; 29(1): 3-133, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25189012

RESUMO

This article synthesizes breast developmental biology and pathophysiology which cause induced abortion to be a risk for breast cancer with the extant epidemiologic studies that differentiate induced and spontaneous abortions. These studies are rigorously statistically analyzed. It also outlines a proposal for the establishment of much-needed data banks that will be able to supply gold-standard prospective data for all breast cancer risks. We recommend collecting longitudinal data though the use of National Accreditation Program for Breast Centers (NAPBC)-approved mammography centers, which can also be linked to a corresponding tissue bank. The data is greatly needed to control the cost of mass mammography screening by identifying those women who are at higher risk of breast cancer and in need of regular or early screening. It is the authors' hope that through this rigorously referenced review, analysis, and proposal that medical science will be advanced and both medical professionals and the lay public will understand the risks contributing to the continued epidemic of breast cancer both here and abroad.


Assuntos
Aborto Induzido/efeitos adversos , Neoplasias da Mama/etiologia , Neoplasias da Mama/prevenção & controle , Aborto Espontâneo , Viés , Mama/fisiologia , Aleitamento Materno , Feminino , Humanos , Lactente , Lactação/fisiologia , Gravidez , Prevenção Primária , Projetos de Pesquisa , Fatores de Risco
5.
Bioorg Med Chem Lett ; 21(21): 6608-12, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21958540

RESUMO

Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D(2) receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eosinophil shape change assay, as well as good oral bioavailability in rat and dog, and efficacy in a mouse model of allergic rhinitis following oral dosing.


Assuntos
Modelos Animais de Doenças , Descoberta de Drogas , Fenilacetatos/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Rinite Alérgica Perene/tratamento farmacológico , Animais , Disponibilidade Biológica , Cães , Camundongos , Fenilacetatos/química , Fenilacetatos/farmacocinética , Fenilacetatos/uso terapêutico , Ratos
6.
J Pharmacol Exp Ther ; 332(3): 764-75, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19996299

RESUMO

Prostaglandin D(2) (PGD(2)) is one of a family of biologically active lipids derived from arachidonic acid via the action of COX-1 and COX-2. PGD(2) is released from mast cells and binds primarily to two G protein-coupled receptors, namely DP1 and DP2, the latter also known as chemoattractant receptor-homologous molecule expressed on Th2 cells. DP2 is predominantly expressed on eosinophils, Th2 cells, and basophils, but it is also expressed to a lesser extent on monocytes, mast cells, and epithelial cells. Interaction of PGD(2) and its active metabolites with DP2 results in cellular chemotaxis, degranulation, up-regulation of adhesion molecules, and cytokine production. Chronic obstructive pulmonary disease (COPD) is a chronic progressive inflammatory disease characterized by elevated lung neutrophils, macrophages, and CD8+ T lymphocytes and mucus hypersecretion. Cigarette smoke contributes to the etiology of COPD and was used here as a provoking agent in a murine model of COPD. In an acute model, {2'-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4'-trifluoro-methyl-biphenyl-3-yl}-acetic acid, sodium salt (AM156) and (5-{2-[(benzoyloxycarbonyl-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid, sodium salt) (AM206), potent DP2 receptor antagonists, dose-dependently inhibited influx of neutrophils and lymphocytes to smoke-exposed airways. In a subchronic model, AM156 and AM206 inhibited neutrophil and lymphocyte trafficking to the airways. Furthermore, AM156 and AM206 treatment inhibited mucus cell metaplasia and prevented the thickening of the airway epithelial layer induced by cigarette smoke. These data suggest that DP2 receptor antagonism may represent a novel therapy for COPD or other conditions characterized by neutrophil influx, mucus hypersecretion, and airway remodeling.


Assuntos
Pulmão/efeitos dos fármacos , Muco/metabolismo , Doença Pulmonar Obstrutiva Crônica/prevenção & controle , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Mucosa Respiratória/efeitos dos fármacos , Fumar/efeitos adversos , Animais , Benzilaminas/farmacocinética , Benzilaminas/farmacologia , Linhagem Celular , Movimento Celular , Feminino , Cobaias , Humanos , Técnicas In Vitro , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/prevenção & controle , Pulmão/imunologia , Pulmão/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Masculino , Metaplasia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Niacina/análogos & derivados , Niacina/farmacocinética , Niacina/farmacologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , Mucosa Respiratória/patologia
7.
Bioorg Med Chem Lett ; 19(16): 4647-51, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19608418

RESUMO

The synthesis of a series of tricyclic antagonists for the prostaglandin D(2) receptor DP2 (CRTH2) is disclosed. The activities of the compounds were evaluated in a human DP2 binding assay and a human whole blood eosinophil shape change assay. Potential metabolic liabilities of the compounds were addressed through in vitro CYP studies. The lead compound was demonstrated to have efficacy in a mouse model of allergic rhinitis following oral dosing.


Assuntos
Antialérgicos/química , Anti-Inflamatórios/química , Compostos Heterocíclicos com 3 Anéis/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Rinite Alérgica Perene/tratamento farmacológico , Animais , Antialérgicos/síntese química , Antialérgicos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Feminino , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Camundongos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-15892257

RESUMO

3'-Azido-3',5-dideoxythymidine 5'-phosphonate and 3',5'-dideoxy-5'-difluoromethylenethymidine 5'-phosphonate were prepared by multistep syntheses. The nucleoside 5'-phosphonates were converted to their triphosphates and triphosphate mimics (P3Ms) containing beta,gamma-difluoromethylene, beta,gamma-dichloromethylene, or beta,gamma-imodo by condensation with pyrophosphate or pyrophosphate mimics, respectively. Inhibition of HIV-1 reverse transcriptase by the nucleoside P3Ms is briefly discussed.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Mimetismo Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Timidina/análogos & derivados , Nucleotídeos de Timina/síntese química , Zidovudina/análogos & derivados , Didesoxinucleotídeos , Estrutura Molecular , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade , Timidina/síntese química , Timidina/química , Timidina/farmacologia , Nucleotídeos de Timina/química , Nucleotídeos de Timina/farmacologia , Zidovudina/síntese química , Zidovudina/química , Zidovudina/farmacologia
9.
J Med Chem ; 48(7): 2695-700, 2005 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-15801860

RESUMO

The triphosphates of antiviral 2',3'-dideoxynucleosides (ddNs) are the active chemical species that inhibit viral DNA synthesis. The inhibition involves incorporation of ddNMP into DNA and subsequent chain termination. A conceivable strategy for antiviral drugs is to employ nucleoside 5'-triphosphate mimics that can entirely bypass cellular phosphorylation. AZT 5'-alpha-R(P)-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaB-betagammaCF(2)TP) has been identified as a potent inhibitor of HIV-1 reverse transcriptase (HIV-1 RT). This work was aimed at confirming that 5'-alphaB-betagammaCF(2)TP is a useful generic triphosphate moiety and can render antiviral ddNs with potent inhibitory effects on HIV-1 RT. Thus, 10 ddNs were converted to their 5'-alphaB-betagammaCF(2)TPs via a sequence (one-pot) of reactions: formation of an activated phosphite, formation of a cyclic triphosphate, boronation, and hydrolysis. Other synthetic routes were also explored. All ddN 5'-alphaB-betagammaCF(2)TPs tested exhibited essentially the same level of inhibition of HIV-1 RT as the corresponding ddNTPs. A conclusion can be made that 5'-alphaB-betagammaCF(2)TP is a generic and promising triphosphate mimic (P3M) concerning HIV-1 RT inhibition and serum stability. It is anticipated that use of 5'-alphaB-betagammaCF(2)TP as P3M moiety will lead to the discovery of a new class of anti-HIV agents.


Assuntos
Fármacos Anti-HIV/síntese química , Compostos de Boro/síntese química , Desoxirribonucleotídeos/síntese química , Transcriptase Reversa do HIV/metabolismo , Inibidores da Transcriptase Reversa/síntese química , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Compostos de Boro/química , Compostos de Boro/metabolismo , Bovinos , Desoxirribonucleotídeos/química , Desoxirribonucleotídeos/metabolismo , Técnicas In Vitro , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/metabolismo , Estereoisomerismo
10.
Nucleosides Nucleotides Nucleic Acids ; 24(10-12): 1651-64, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16438041

RESUMO

Nucleoside reverse transcriptase inhibitors (NRTIs) are prodrugs which require three intracellular phosphorylation steps to yield their corresponding, biologically active, nucleoside triphosphate. In order to circumvent this often inefficient phosphorylation cascade, a plausible approach is to provide the active species directly in the form of a stabilized nucleoside triphosphate mimic. We have previously shown that such a mimic, namely 5'-alpha-Rp-borano-beta,gamma-(difluoromethylene)triphosphate (5'-alphaBCF2TP) is a generic triphosphate mimic that is biologically stable and can render antiviral ddNs with potent inhibitory activity against HIV-1 RT. Herein we report the synthesis and activity against HIV-1 RT of several ddN 5'-alpha-modified-beta,gamma(difluoromethylene)triphosphate mimics with either a non-bridging calphaP-thio (5'-alphaSCF2TP) or alpha-P-seleno (5'-alpha SeCF2TP) modification. One compound, namely, AZT-5'-alpha-P-seleno-beta,gamma-(difluoromethylene)triphosphate (diastereomer I), was identified as a potent inhibitor of HIV-1 RT (Ki = 64 nM) and represents the first report of HIV-1 RT inhibition data for a nucleotide bearing an alpha-P-seleno modification. These triphosphate mimics may be useful in the investigation of enzyme mechanism and may have interesting properties with respect to drug resistance and polymerase selectivity.


Assuntos
Fármacos Anti-HIV/síntese química , Didesoxinucleosídeos/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Compostos Organosselênicos/síntese química , Inibidores da Transcriptase Reversa/síntese química , Sulfetos/síntese química , Fármacos Anti-HIV/química , Didesoxinucleosídeos/química , Transcriptase Reversa do HIV/química , Compostos Organosselênicos/química , Inibidores da Transcriptase Reversa/química , Sulfetos/química
11.
J Med Chem ; 47(27): 6902-13, 2004 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-15615539

RESUMO

In search of active nucleoside 5'-triphosphate mimics, we have synthesized a series of AZT triphosphate mimics (AZT P3Ms) and evaluated their inhibitory effects on HIV-1 reverse transcriptase as well as their stability in fetal calf serum and in CEM cell extracts. Reaction of AZT with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one, followed by treatment of the phosphite intermediate 2 with pyrophosphate analogues, yielded the cyclic triphosphate intermediates 4b-4f, which were subjected to boronation and subsequent hydrolysis to give AZT 5'-alpha-borano-beta,gamma-bridge-modified triphosphates 6b-6f in moderate to good yields. Reaction of the cyclic intermediate 4d with iodine, followed by treatment with a series of nucleophiles, afforded the AZT 5'-beta,gamma-difluoromethylene-gamma-substituted triphosphates (7b-7i). Several different types of AZT P3Ms containing alpha-P-thio (or dithio) and beta,gamma-difluoromethylene (13,14), alpha,beta-difluoromethylene and gamma-P-methyl(or phenyl) (15,16), and alpha-borano-beta,gamma-difluoromethylene and gamma-O-methyl/phenyl (11,12) were also synthesized. The effectiveness of the compounds as inhibitors of HIV-1 reverse transcriptase was determined using a fluorometric assay and a poly(A) homopolymer as a template. A number of AZT P3Ms exhibited very potent inhibition of HIV-1 reverse transcriptase. Modifications at the beta,gamma-bridge of triphosphate rendered the AZT P3Ms 6b-6f with varied activities (K(i) from 9.5 to >>500 nM) while modification at the alpha,beta-bridge of triphosphate led to weak AZT P3M inhibitors. The results imply that the AZT P3Ms were substrate inhibitors, as is AZT triphosphate. The most active compound, AZT 5'-alpha-R(p)()-borano-beta,gamma-(difluoromethylene)triphosphate (AZT 5'-alphaB-betagammaCF(2)TP) (6d-I), is as potent as AZT triphosphate with a K(i)() value of 9.5 nM and at least 20-fold more stable than AZT triphosphate in the serum and cell extracts. Therefore, for the first time, a highly active and stable nucleoside triphosphate mimic has been identified, which is potentially useful as a new type of antiviral drug. The promising triphosphate mimic, 5'-alpha-borano-beta,gamma-(difluoromethylene)triphosphate, is expected to be valuable to the discovery of nucleotide mimic antiviral drugs.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/síntese química , Zidovudina/análogos & derivados , Estabilidade de Medicamentos , Humanos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
12.
Artigo em Inglês | MEDLINE | ID: mdl-15043157

RESUMO

IMPDH inhibitors have potential antimicrobial, anticancer and immunomodulatory effects. Nucleoside inhibitors of IMPDH exert their inhibitory effects via nucleoside 5'-MPs. Conversion of nucleoside analogs to NMPs by cellular nucleoside kinases is not assured, and usually is inefficient. In order to bypass cellular phosphorylation, a series of azole nucleoside 5'-MP mimics (P1Ms) based on ribavirin, EICAR and bredinin were synthesized and screened against human and C. albicans IMP dehydrogenises. P1Ms 8, 16, 25, 28 and 29 demonstrated substantial IMPDH inhibition with Ki values in low micromolar range.


Assuntos
Inibidores Enzimáticos/síntese química , IMP Desidrogenase/antagonistas & inibidores , Nucleotídeos/síntese química , Inibidores Enzimáticos/química , Nucleotídeos/química
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