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1.
Cancer Treat Rev ; 81: 101912, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31715423

RESUMO

Regorafenib is a multi-targeting kinase inhibitor approved for the treatment of metastatic colorectal cancer patients in refractory to standard chemotherapy. Similarly to sorafenib, this agent was originally developed as a RAF1 inhibitor. However, the kinase inhibitory profile is distinct from sorafenib. A broad-spectrum of kinase inhibition induces wide-range drug sensitivity, irrespective of mutation status of major oncogenes. This agent's main therapeutic effects are anti-angiogenesis and the remodeling of tumor microenvironment through several mechanisms of action. The dual blockade of VEGF receptors and TIE2 can lead to both additive anti-angiogenesis effects and the suggestive unique regulation of vessel stability. Additionally, it inhibits molecular escape pathways to VEGF inhibition (e.g., FGF, PIGF, and PDGF signaling), enabling its continuous antiangiogenic effect even in tumors resistant to VEGF inhibitors. Furthermore, regorafenib has the important effect of enhancing anti-tumor immunity via macrophage modulation. Based on this concept, clinical trials have been recently launched for the development of a combination strategy with immune checkpoint inhibitors. Contrary to regorafenib induced clinical benefits and advances in the novel strategy, currently no predictive biomarkers have been identified. In the present review, we revisit and summarize regorafenib's unique mechanisms of action. The review could highlight molecular insights and provide some perspective for the search of predictive biomarkers used in metastatic colorectal cancer patients treated with regorafenib.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Inibidores da Angiogênese/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Mutação , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Receptor TIE-2/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Proteínas ras/genética
2.
Eur J Med Chem ; 164: 440-447, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30616052

RESUMO

Aberrant angiogenesis is a hallmark of various diseases including cancers. VEGFR-2 inhibitors have been utilized as anti-angiogenic agents for several years. However, compensatory activation of various receptor tyrosine kinases (RTK) could induce the occurrence of resistance. We previously reported a series of multi-target inhibitors of VEGFR-2, Tie-2, and EphB4 as anti-angiogenic agents. These inhibitors might be a promising strategy to overcome the resistance induced by compensatory activation. In order to expand the structural diversity of these multiple RTK inhibitors, we described herein the design, synthesis, and evaluation of a novel class of triplet VEGFR-2/TIE-2/EphB4 inhibitors. The biological evaluation indicated that five compounds (6b, 6d, 6e, 7e, and 7g) exhibited simultaneous VEGFR-2/Tie-2/EphB4 inhibitory activities with IC50 values less than 50 nM.


Assuntos
Inibidores da Angiogênese/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Humanos , Concentração Inibidora 50 , Inibidores de Proteínas Quinases/síntese química , Receptor EphB4/antagonistas & inibidores , Receptor TIE-2/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
3.
Eur J Med Chem ; 163: 1-9, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503935

RESUMO

VEGFR-2, Tie-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we developed a series of pyridines incorporated with 1,2,3-triazole as multi-target inhibitors based on the crystal structure alignment of the kinase domain of angiogenic RTKs. Biological results indicated that these multi-target inhibitors displayed considerable potential as novel anti-angiogenic agents. Among them, compound BD7 exhibited the most potent inhibition against the three RTKs simultaneously, and good activity on inhibiting viability of human umbilical endothelial cells. Therefore, 1,2,3-triazole could serve as a promising DFG binding group for multi-target inhibitors of VEGFR-2, Tie-2 and EphB4 bearing pyridine as hinge binding group.


Assuntos
Inibidores da Angiogênese/síntese química , Piridinas/química , Receptor EphB4/antagonistas & inibidores , Receptor TIE-2/antagonistas & inibidores , Triazóis/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Quinases
4.
Bioorg Med Chem ; 26(21): 5596-5611, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30385226

RESUMO

Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-d]pyrimidine octamides (4a-o and 6a-g) and their corresponding free amines 5a-m and 7a-g have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides 6d-g as well as the amine derivative 7b have shown the best anticancer activity with single digit micromolar GI50 values over the tested cancer cells, and low cytotoxic effects (GI50 > 10.0 µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-d]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member 6f was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI50 and TGI values over multiple cancer cells. Kinase profile of compound 6f over 53 oncogenic kinases at 10 µM concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of 6f against TrkA (IC50 = 2.25 µM), FGFR4 (IC50 = 6.71 µM) and Tie2 (IC50 = 6.84 µM) was explained by molecular docking study, which also proposed that 6f may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound 6f may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/farmacocinética , Pirróis/síntese química , Pirróis/química , Pirróis/farmacocinética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/química , Receptor TIE-2/antagonistas & inibidores , Receptor TIE-2/química , Receptor trkA/antagonistas & inibidores , Receptor trkA/química
5.
Cell Signal ; 51: 211-221, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30077653

RESUMO

The inflammatory response is essential for eradication of lipopolysaccharide (LPS) presenting microbial invaders but requires exquisite regulation to prevent detrimental vascular inflammation. Endothelial cells play active roles in both the initiation of inflammation, through the detection of LPS by Toll-like Receptor 4 (TLR4), and the resolution of inflammation, through the actions of the receptor tyrosine kinase, Tie2. The process by which Tie2 attenuates LPS-TLR4 driven inflammation is poorly understood. To investigate the effects of Tie2 on TLR4 signalling, Nf-κB activation was monitored in cells expressing Tie2 mutants harboring tyrosine (Y) to phenylalanine (F) substitutions in the cytoplasmic domain. Tie2 attenuated LPS induced Nf-κB activation in a manner requiring Tie2 kinase activation, the carboxy-terminal tyrosine residue Y1100 and downstream Erk1/2 signalling. Tyrosine 1100 was also required for the Tie2 dependent decrease in expression of the TLR4 signalling proteins, TRAF6 and IRAK1 and stabilization of the Nf-κB inhibitor, IκBα. In contrast, upregulation of known TLR4 antagonist miRNA-146b-5p required all three tyrosine phosphorylation sites in Tie2. Finally, we confirmed in an in vivo model that activation of Tie2 signalling reduces LPS mediated inflammation. Our results show that Y1100 initiated Erk1/2 signalling is essential for the anti-inflammatory effect of Tie2 on TLR4 mediated inflammation.


Assuntos
Inflamação/imunologia , Receptor TIE-2/fisiologia , Receptor 4 Toll-Like/imunologia , Animais , Células Endoteliais , Células HEK293 , Humanos , Quinases Associadas a Receptores de Interleucina-1/imunologia , Lipopolissacarídeos/imunologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos , Modelos Animais , Inibidor de NF-kappaB alfa/imunologia , NF-kappa B/imunologia , Receptor TIE-2/antagonistas & inibidores , Fator 6 Associado a Receptor de TNF/imunologia
6.
BMC Biol ; 16(1): 92, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-30119679

RESUMO

BACKGROUND: Increased activity of the receptor tyrosine kinase Tie2 has been implicated in the promotion of pathological angiogenesis. This activity is mainly mediated through angiopoietin (Ang)1- and Ang2-dependent activation of integrins by Tie2, rendering the Ang/Tie2/integrin axis an attractive putative target for cancer therapeutics. RESULTS: To target this axis, we developed single domain, non-immunoglobulin high-affinity bi-specific protein inhibitors against both Tie2 and αvß3 integrin. We have previously engineered the Ang2-binding domain of Tie2 (Ang2-BD) as a Tie2 inhibitor. Here, we engineered an exposed loop in Ang2-BD to generate variants that include an integrin-binding Arg-Gly-Asp (RGD) motif and used flow cytometry screening of a yeast-displayed Ang2-BD RGD loop library to identify the integrin antagonists. The bi-specific antagonists targeting both Tie2 and αvß3 integrin inhibited adhesion and proliferation of endothelial cells cultured together with the αvß3 integrin ligand vitronectin, as well as endothelial cell invasion and tube formation. The bi-specific reagents inhibited downstream signaling by Tie2 intracellularly in response to its agonist Ang1 more effectively than the wild-type Ang2 BD that binds Tie2 alone. CONCLUSIONS: Collectively, this study-the first to describe inhibitors targeting all the known functions resulting from Tie2/integrin αvß3 cross-talk-has created new tools for studying Tie2- and integrin αvß3-dependent molecular pathways and provides the basis for the rational and combinatorial engineering of ligand-Tie2 and ligand-integrin αvß3 receptor interactions. Given the roles of these pathways in cancer angiogenesis and metastasis, this proof of principle study paves the route to create novel Tie2/integrin αvß3-targeting proteins for clinical use as imaging and therapeutic agents.


Assuntos
Inibidores da Angiogênese/farmacologia , Neovascularização Fisiológica/genética , Receptor TIE-2/antagonistas & inibidores , Receptores de Vitronectina/genética , Ribonuclease Pancreático/antagonistas & inibidores , Inibidores da Angiogênese/química , Animais , Camundongos , Receptor TIE-2/química , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Receptores de Vitronectina/química , Receptores de Vitronectina/metabolismo , Ribonuclease Pancreático/química , Ribonuclease Pancreático/genética , Ribonuclease Pancreático/metabolismo
7.
Basic Clin Pharmacol Toxicol ; 123 Suppl 5: 6-19, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29668117

RESUMO

Vascular anomalies are localized defects of morphogenesis that can affect lymphatic and blood vessels. They are generally called birthmarks, typically observed soon after birth and occurring in up to 10% of children. Based on their clinical and histological characteristics, they are classified into vascular tumours and vascular malformations. The most common malformations are venous malformations (VMs) resulting in chronic vascular diseases that can be associated with significant morbidity necessitating often demanding and repeating clinical management. The current treatment is based on surgical resection and sclerotherapy, which can be impossible due to the size or location of lesions or ineffective due to the regrowth of malformed vessels. Therefore, medical therapies for VMs are highly desired. Recent studies have identified genetic defects that result in the constantly active endothelial cell receptor tyrosine kinase TIE2/phosphoinositide 3-kinase PI3K signalling pathway as a frequent cause for VMs. The first treatment to inhibit this pathway with sirolimus indicated that molecular treatment can be effective against VMs. In addition, certain VM 'hotspot' mutations have been previously found in tumours, providing the rationale for the exploration and repurposing of existing and investigational cancer drugs for VMs. Finally, discoveries of molecular and cellular abnormalities that characterize a large proportion of VMs and the generation of pre-clinical VM mouse models provide the necessary basis for the development of the targeted molecular treatment strategies we discuss in this MiniReview.


Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Doenças Vasculares/prevenção & controle , Malformações Vasculares/tratamento farmacológico , Veias/anormalidades , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Doença Crônica/prevenção & controle , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Modelos Animais de Doenças , Humanos , Terapia de Alvo Molecular/métodos , Mutação , Inibidores de Proteínas Quinases/farmacologia , Receptor TIE-2/antagonistas & inibidores , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Doenças Vasculares/etiologia , Malformações Vasculares/complicações , Malformações Vasculares/genética
8.
Sci Rep ; 8(1): 505, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29323190

RESUMO

Angiopoietin-1 (Ang1) and Angiopoietin-2 (Ang2) are ligands for Tie2, an endothelial-specific receptor tyrosine kinase that is an essential regulator of angiogenesis. Here we report the identification, via expression cloning, of thrombomodulin (TM) as another receptor for Ang1 and Ang2. Thrombomodulin is an endothelial cell surface molecule that plays an essential role as a coagulation inhibitor via its function as a cofactor in the thrombin-mediated activation of protein C, an anticoagulant protein, as well as thrombin-activatable fibrinolysis inhibitor (TAFI). Ang1 and Ang2 inhibited the thrombin/TM-mediated generation of activated protein C and TAFI in cultured endothelial cells, and inhibited the binding of thrombin to TM in vitro. Ang2 appears to bind TM with higher affinity than Ang1 and is a more potent inhibitor of TM function. Consistent with a potential role for angiopoietins in coagulation, administration of thrombin to mice rapidly increased plasma Ang1 levels, presumably reflecting release from activated platelets (previously shown to contain high levels of Ang1). In addition, Ang1 levels were significantly elevated in plasma prepared from wound blood, suggesting that Ang1 is released from activated platelets at sites of vessel injury. Our results imply a previously undescribed role for angiopoietins in the regulation of hemostasis.


Assuntos
Angiopoietina-1/metabolismo , Angiopoietina-2/metabolismo , Trombina/metabolismo , Trombomodulina/metabolismo , Angiopoietina-1/sangue , Angiopoietina-1/genética , Angiopoietina-2/genética , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Células COS , Carboxipeptidase B2/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fator Plaquetário 4/metabolismo , Ligação Proteica , Proteína C/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor TIE-2/antagonistas & inibidores , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Trombina/química , Trombina/farmacologia , Trombomodulina/genética
9.
Eur J Med Chem ; 141: 506-518, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29102175

RESUMO

Herein, we embarked on a structural optimization campaign aiming at the discovery of second generation anti-angiogenesis agents with our previously reported BPS-7 as lead compound. A library of 27 compounds has been afforded based on the highly conserved ATP-binding pocket of VEGFR-2, Tie-2, and EphB4. Several title compounds exhibited simultaneous inhibitory effects against three angiogenic RTKs. These compounds with a 'triplet' inhibition profile have been identified as novel anti-angiogenic and anticancer agents. The representative VDAU11 displayed prominent anti-angiogenic and anticancer potency and could be considered as a candidate for further optimization. These results indicate that N-(pyridin-2-yl)acrylamide could serve as a novel hinge-binding group of triple inhibitors.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor EphB4/antagonistas & inibidores , Receptor TIE-2/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptor EphB4/metabolismo , Receptor TIE-2/metabolismo , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
11.
Mol Cancer Ther ; 16(11): 2486-2501, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28838996

RESUMO

Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients. Mol Cancer Ther; 16(11); 2486-501. ©2017 AACR.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Receptor TIE-2/antagonistas & inibidores , Angiopoietinas/antagonistas & inibidores , Angiopoietinas/genética , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Quinolinas/uso terapêutico , Receptor TIE-2/genética , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
12.
Oncotarget ; 8(20): 33571-33585, 2017 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-28422724

RESUMO

In many human cancers, the receptor tyrosine kinase (RTK) Tie2 plays important roles in mediating proliferation, survival, migration and angiogenesis. Thus, molecules that could potently inhibit activation of the Tie2 receptor would have a significant impact on cancer therapy. Nevertheless, attempts to develop Tie2-targeted inhibitors have met with little success, and there is currently no FDA-approved therapeutic selectively targeting Tie2. We used a combinatorial protein engineering approach to develop a new generation of angiopoietin (Ang)2-derived Tie2 antagonists as potential cancer therapeutics and as tools to study angiogenesis. The construct for designing a yeast surface display (YSD) library of potential antagonists was an Ang2 binding domain (Ang2-BD) that retains Tie2 binding ability but prevents ligand multimerization and receptor dimerization and activation. This mutant library was then screened by quantitative high-throughput flow cytometric sorting to identify Ang2-BD variants with increased expression, stability and affinity to Tie2. The selected variants were recombinantly expressed and showed high affinity to soluble and cellular Tie2 and strongly inhibited both Tie2 phosphorylation and endothelial capillary tube formation and cell invasion compared to the parental Ang2-BD. The significance of the study lies in the insight it provides into the sequence-structure-function relationships and mechanism of action of the antagonistic Ang mutants. The approach of using a natural protein ligand as a molecular scaffold for engineering high-affinity agents can be applied to other ligands to create functional protein antagonists against additional biomedical targets.


Assuntos
Inibidores da Angiogênese/farmacologia , Angiopoietina-2/metabolismo , Neovascularização Patológica/metabolismo , Receptor TIE-2/antagonistas & inibidores , Inibidores da Angiogênese/química , Angiopoietina-2/química , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Receptor TIE-2/química , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
13.
Actas Dermosifiliogr ; 108(6): 515-523, 2017.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28162227

RESUMO

Angiogenesis is the growth of new blood vessels from pre-existing vessels. It is a biological process essential in physiological wound healing or pathological inflammation and tumor growth, which underlies a complex interplay of stimulating and inhibiting signals. Extracellular matrix, cells of innate and adaptive immunity and endothelial cells itself are a major source of angiogenic factors that activate or inhibit specific receptors and consequently influence intracellular signaling pathways. Most inflammatory and neoplastic diseases in dermatology are characterized by excessive angiogenesis, such as psoriasis, atopic dermatitis, as well as melanoma, non-melanoma skin cancer, but also benign vascular neoplasia. In this article we describe current knowledge of angiogenesis and its most relevant mechanisms in different dermatological disorders with particular emphasis on the angiogenic factors (vascular endothelial growth factor) and angiopoietins as a target of current and future directions of anti-angiogenic therapy.


Assuntos
Neovascularização Patológica/etiologia , Neovascularização Fisiológica , Dermatopatias/complicações , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Proteínas Angiogênicas/fisiologia , Angiopoietinas/antagonistas & inibidores , Angiopoietinas/fisiologia , Resistencia a Medicamentos Antineoplásicos , Hemangioma/tratamento farmacológico , Hemangioma/fisiopatologia , Humanos , Melanoma/complicações , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/fisiopatologia , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/fisiologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/fisiopatologia , Psoríase/tratamento farmacológico , Psoríase/fisiopatologia , Receptor TIE-2/antagonistas & inibidores , Receptor TIE-2/fisiologia , Pele/irrigação sanguínea , Dermatopatias/imunologia , Dermatopatias/fisiopatologia , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/fisiopatologia
14.
J Chem Inf Model ; 57(2): 345-354, 2017 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-28079371

RESUMO

The anomalous binding modes of five highly similar fragments of TIE2 inhibitors, showing three distinct binding poses, are investigated. We report a quantitative rationalization for the changes in binding pose based on molecular dynamics simulations. We investigated five fragments in complex with the transforming growth factor ß receptor type 1 kinase domain. Analyses of these simulations using Grid Inhomogeneous Solvation Theory (GIST), pKA calculations, and a tool to investigate enthalpic differences upon binding unraveled the various thermodynamic contributions to the different binding modes. While one binding mode flip can be rationalized by steric repulsion, the second binding pose flip revealed a different protonation state for one of the ligands, leading to different enthalpic and entropic contributions to the binding free energy. One binding pose is stabilized by the displacement of entropically unfavored water molecules (binding pose determined by solvation entropy), ligands in the other binding pose are stabilized by strong enthalpic interactions, overcompensating the unfavorable water entropy in this pose (binding pose determined by enthalpic interactions). This analysis elucidates unprecedented details determining the flipping of the binding modes, which can elegantly explain the experimental findings for this system.


Assuntos
Entropia , Receptor TIE-2/metabolismo , Descoberta de Drogas , Simulação de Dinâmica Molecular , Ligação Proteica , Domínios Proteicos , Receptor TIE-2/antagonistas & inibidores , Solventes/química , Água/química
15.
Clin Cancer Res ; 23(10): 2405-2413, 2017 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-27821605

RESUMO

Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma patients.Experimental Design: In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival.Results: The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS.Conclusions: Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib. Clin Cancer Res; 23(10); 2405-13. ©2016 AACR.


Assuntos
Anilidas/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Interleucina-6/sangue , Interleucina-8/sangue , Neoplasias Hepáticas/tratamento farmacológico , Quinolinas/administração & dosagem , Adulto , Idoso , Anilidas/farmacocinética , Biomarcadores Farmacológicos/sangue , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinolinas/farmacocinética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor TIE-2/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores
16.
J Neurochem ; 140(1): 170-182, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27787897

RESUMO

Targeting the vascular endothelial growth factor signaling axis in glioblastoma inevitably leads to tumor recurrence and a more aggressive phenotype. Therefore, other angiogenic pathways, like the angiopoietin/tunica interna endothelial cell kinase (TIE) signaling axis, have become additional targets for therapeutic intervention. Here, we explored whether targeting the receptor tyrosine kinase TIE-2 using a novel, highly potent, orally available small molecule TIE-2 inhibitor (BAY-826) improves tumor control in syngeneic mouse glioma models. BAY-826 inhibits TIE-2 phosphorylation in vitro and in vivo as demonstrated by suppression of Angiopoietin-1- or Na3 VO4 -induced TIE-2 phosphorylation in glioma cells or extracts of lungs from BAY-826-treated mice. There was a trend toward prolonged survival upon single-agent treatment in two of four models (SMA-497 and SMA-540) and there was a significant survival benefit in one model (SMA-560). Co-treatment with BAY-826 and irradiation was ineffective in one model (SMA-497), but provided synergistic prolongation of survival in another (SMA-560). Decreased vessel densities and increased leukocyte infiltration were observed, but might be independent processes as the effect was also observed in single treatment modalities. These data demonstrate that TIE-2 inhibition may improve tumor response to treatment in highly vascularized tumors such as glioblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/enzimologia , Modelos Animais de Doenças , Glioma/enzimologia , Receptor TIE-2/antagonistas & inibidores , Receptor TIE-2/metabolismo , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Glioma/tratamento farmacológico , Isoenxertos , Camundongos , Camundongos Endogâmicos C57BL , Resultado do Tratamento , Carga Tumoral
17.
Sci Rep ; 6: 37628, 2016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27876862

RESUMO

The receptor tyrosine kinase Tie-2 is involved in vessel remodeling and maturation, and has been regarded as a potential target for the treatment of various solid tumors. The absence of novel, potent and selective inhibitors severely hampers the understanding of the therapeutic potential of Tie-2. In the present work, we describe the discovery of novel type-I inhibitors of Tie-2 by structure-based virtual screening. Preliminary SAR was also performed based on one active compound, and several novel inhibitors with low micro-molar affinity were discovered. To directly compare the efficiency between different filtering strategies in selecting VS candidates, two methods were separately carried out to screen the same chemical library, and the selected VS candidates were then experimentally assessed by in vitro enzymatic assays. The results demonstrate that the hit rate is improved when stricter drug-likeness criteria and less number of molecules for clustering analysis are used, and meanwhile, the molecular diversity of the compounds still maintains. As a case study of TIE-2, the information presented in this work underscores the importance of selecting an appropriate selection strategy in VS campaign, and the novel inhibitors identified and the detailed binding modes of action provide a starting point for further hit-to-lead optimization process.


Assuntos
Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Inibidores de Proteínas Quinases/farmacologia , Receptor TIE-2/antagonistas & inibidores , Interface Usuário-Computador , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/química , Receptor TIE-2/metabolismo , Relação Estrutura-Atividade
18.
Curr Diab Rep ; 16(12): 126, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27778249

RESUMO

Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization. AKB-9778 is a small-molecule antagonist of VE-PTP which increases phosphorylation of Tie2 even in the presence of high Angpt2 levels. In preclinical studies, AKB-9778 reduced VEGF-induced leakage and ocular neovascularization (NV) and showed additive benefit when combined with VEGF suppression. In two clinical trials in diabetic macular edema (DME) patients, subcutaneous injections of AKB-9778 were safe and provided added benefit to VEGF suppression. Preliminary data suggest that AKB-9778 monotherapy improves diabetic retinopathy. These data suggest that Tie2 activation may be a valuable strategy to treat or prevent diabetic retinopathy.


Assuntos
Compostos de Anilina/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Edema Macular/tratamento farmacológico , Receptor TIE-2/antagonistas & inibidores , Ácidos Sulfônicos/uso terapêutico , Angiopoietina-1/fisiologia , Angiopoietina-2/fisiologia , Humanos , Receptor TIE-2/fisiologia , Proteínas Tirosina Fosfatases Classe 3 Semelhantes a Receptores/fisiologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Cancer Res ; 76(16): 4841-4849, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27287719

RESUMO

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal hematopoietic activity in part by enabling a pathogenic inflammatory milieu in the bone marrow. In this report, we show that elevation of angiopoietin-1 in myelodysplastic CD34(+) stem-like cells is associated with higher risk disease and reduced overall survival in MDS and AML patients. Increased angiopoietin-1 expression was associated with a transcriptomic signature similar to known MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the angiopoietin-1 receptor Tie-2, which was also found to inhibit the proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib inhibited leukemic proliferation, prevented activation of downstream effector kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells. Notably, treatment of primary MDS specimens with this compound stimulated hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer Res; 76(16); 4841-9. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Indazóis/farmacologia , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/patologia , Receptor TIE-2/antagonistas & inibidores , Ureia/análogos & derivados , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Angiopoietina-1/metabolismo , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Modelos de Riscos Proporcionais , Ureia/farmacologia
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