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1.
Cell Mol Life Sci ; 80(4): 104, 2023 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-36947256

RESUMO

Targeted therapy is a new cancer treatment approach, involving drugs that particularly target specific proteins in cancer cells, such as receptor tyrosine kinases (RTKs) which are involved in promoting growth and proliferation, Therefore inhibiting these proteins could impede cancer progression. An understanding of RTKs and the relevant signaling cascades, has enabled the development of many targeted drug therapies employing RTK inhibitors (RTKIs) some of which have entered clinical application. Here we discuss RTK structures, activation mechanisms and functions. Moreover, we cover the potential effects of combination drug therapy (including chemotherapy or immunotherapy agents with one RTKI or multiple RTKIs) especially for drug resistant cancers.


Assuntos
Neoplasias , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais
2.
Cell Commun Signal ; 20(1): 123, 2022 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-35978432

RESUMO

Medulloblastoma is the most common pediatric embryonal brain tumor, and may occur in cancer predisposition syndromes. We describe novel associations of medulloblastoma with atypical prolactinoma and dural high-grade sarcoma in Li-Fraumeni syndrome (LFS), and epidural desmoid fibromatosis in familial adenomatous polyposis (FAP)/Turcot syndrome. Genomic analysis showing XRCC3 alterations suggested radiotherapy as contributing factor to the progression of LFS-associated medulloblastoma, and demonstrated different mechanisms of APC inactivation in the FAP-associated tumors. The integrated genomic-transcriptomic analysis uncovered the growth pathways driving tumorigenesis, including the prolactin-prolactin receptor (PRLR) autocrine loop and Shh pathway in the LFS-associated prolactinoma and medulloblastoma, respectively, the Wnt pathway in both FAP-associated neoplasms, and the TGFß and Hippo pathways in the soft tissue tumors, regardless of germline predisposition. In addition, the comparative analysis of paired syndromic neoplasms revealed several growth pathways susceptible to therapeutic intervention by PARP, PRLR, and selective receptor tyrosine kinase (RTK) inhibitors. These could target the defective DNA damage repair in the LFS-associated medulloblastoma, the prolactin autocrine loop in the atypical prolactinoma, the EPHA3/7 and ALK overexpression in the FAP-associated medulloblastoma, and the multi-RTK upregulation in the soft tissue neoplasms. This study presents the spatiotemporal evolution of novel neoplastic associations in syndromic medulloblastoma, and discusses the post-radiotherapy risk for secondary malignancies in syndromic pediatric patients, with important implications for the biology, diagnosis, and therapy of these tumors. Video Abstract.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias Cerebelares , Meduloblastoma , Neoplasias Hipofisárias , Prolactinoma , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Neoplasias Cerebelares/genética , Criança , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Prolactina
3.
Cancer Cell Int ; 18: 63, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29713246

RESUMO

BACKGROUND: A growing field of evidence suggests the involvement of oncogenic receptor tyrosine kinases (RTKs) in cell transformation. Deregulated activity of RTKs in tumors can determine disease progression and therapeutic responses in several types of cancer, including neuroblastoma (NB). Therefore, RTKs targeting is a worthwhile challenge for the oncologists. Nevertheless, acquired resistance to RTK inhibitors (RTKi) remains a serious problem. Autophagy activation is among the possible obstacles for good efficacy of the therapy with RTKi. METHODS: Under different treatment conditions we measured autophagic flux using immunoblot and immunofluorescence assays. Death induction was validated by trypan blue exclusion assay and FACS analysis (calcein-AM/propidium iodide). The NB cell lines SH-SY5Y and Kelly were used for the in vitro study. RESULTS: In order to define whether autophagy might be a limiting factor for the efficacy of RTKi in NB cells, we firstly checked its activation following the treatment with several RTKi. Next, we investigated the possibility to increase their therapeutic efficiency by combining RTKi with autophagy blocking agents in vitro. We exploited the effectiveness of three RTKi either alone or in combination with autophagy inhibitors (Chloroquine-CQ and Spautin-1). We demonstrated that autophagy induction was drug-dependent, and that its inhibition increased the anti-tumor activity of a single RTKi unevenly. We observed that the combined use of blocking agents which impair late autophagy events, such as CQ, and RTKi can be more effective with respect to the use of RTKi alone. CONCLUSIONS: In the present report, we assessed the conditions under which autophagy is activated during the use of different RTKi currently in the pre-clinical evaluation for NB. We summarized the achievements of combined RTK/autophagy inhibitors treatment as a promising approach to enhance the efficacy of RTKi in impairing tumor cells viability.

4.
Molecules ; 22(12)2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29206199

RESUMO

The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs typically occurs due to several mechanisms that include hemi- or homo-zygous deletion of the wild-type KIT allele, overexpression of focal adhesion kinase (FAK) and insulin-like growth factor receptor I (IGF-1R) amplification, BRAF mutation, a RTK switch (loss of c-KIT and gain of c-MET/AXL), etc. We established and characterized the IM-resistant GIST T-1 cell line (GIST T-1R) lacking secondary c-KIT mutations typical for the IM-resistant phenotype. The resistance to IM in GIST T-1R cells was due to RTK switch (loss of c-KIT/gain of FGFR2α). Indeed, we have found that FGFR inhibition reduced cellular viability, induced apoptosis and affected the growth kinetics of the IM-resistant GISTs in vitro. In contrast, IM-naive GIST T-1 parental cells were not susceptible to FGFR inhibition. Importantly, inhibition of FGF-signaling restored the susceptibility to IM in IM-resistant GISTs. Additionally, IM-resistant GISTs were less susceptible to certain chemotherapeutic agents as compared to parental IM-sensitive GIST cells. The chemoresistance in GIST T-1R cells is not due to overexpression of ABC-related transporter proteins and might be the result of upregulation of DNA damage signaling and repair (DDR) genes involved in DNA double-strand break (DSB) repair pathways (e.g., XRCC3, Rad51, etc.). Taken together, the established GIST T-1R cell subline might be used for in vitro and in vivo studies to examine the efficacy and prospective use of FGFR inhibitors for patients with IM-resistant, un-resectable and metastatic forms of GISTs with the type of RTK switch indicated above.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Células Epiteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-kit/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Anilidas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Crizotinibe , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Quinase 1 de Adesão Focal/genética , Quinase 1 de Adesão Focal/metabolismo , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/farmacologia , Paclitaxel/farmacologia , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais , Vimblastina/farmacologia
5.
Bioorg Med Chem Lett ; 25(17): 3706-10, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26112445
8.
J Cancer Immunol (Wilmington) ; 6(2): 62-69, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39175850

RESUMO

KRAS is a commonly mutated gene in advanced colorectal cancer (CRC). Recently, inhibitors of KRAS G12C were developed and have shown promising efficacy for KRAS G12C mutated non-small cell lung cancer. However, KRAS G12C inhibitor monotherapy has not demonstrated excellent efficacy for KRAS G12C mutated advanced CRC due to multiple resistance mechanisms, especially receptor tyrosine kinase (RTK) signaling activation. To overcome this resistance mechanism, various combinations of epithelial growth factor receptor (EGFR) and KRAS G12C inhibitors, including panitumumab plus sotorasib, have been investigated in clinical trials. The combination of EGFR and KRAS G12C inhibitors for KRAS G12C mutated CRC demonstrated overall response rates ranging from 26% to 62.5% in seven clinical trials of phase I to III, whose data are available so far. The median progression-free survival in these trials ranged from 3.9 to 8.1 months. These efficacy data suggest that KRAS G12C inhibitor combination with EGFR inhibitors is more effective for KRAS G12C mutated advanced CRC than KRAS G12C inhibitor monotherapy. They also showed reasonable safety of the combination regimen. Based on these results, phase III clinical trials are being conducted to investigate EGFR and KRAS G12C inhibitor combinations as a first or second-line treatment for KRAS G12C mutated advanced CRC. Furthermore, other KRAS G12C inhibitors, KRAS G12D inhibitors, and pan-RAS inhibitors are being developed, which could make more patients with advanced CRC eligible for KRAS inhibition.

9.
Front Oncol ; 14: 1380584, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38756650

RESUMO

Although KRAS G12C inhibitors have proven that KRAS is a "druggable" target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical data have suggested additional promising KRAS G12C combinations with YAP/TAZ-TEAD inhibitors, FAK inhibitors, and farnesyltransferase inhibitors. The combinations of KRAS G12C inhibitors with immunotherapies and chemotherapies have also been investigated, and the preliminary results were reported. More recently, KRAS-targeted therapies not limited to KRAS G12C are being developed, potentially broadening the treatment landscape of KRAS-mutated cancers. Rationally combining KRAS inhibitors with other therapeutics is likely to play a significant role in future treatment for KRAS-mutated solid tumors.

10.
Arch Pharm Res ; 47(6): 538-557, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38902481

RESUMO

Age-related macular degeneration (AMD) is the leading cause of vision loss in senior adults. The disease can be categorized into two types: wet AMD and dry AMD. Wet AMD, also known as exudative or neovascular AMD, is less common but more severe than dry AMD and is responsible for 90% of the visual impairment caused by AMD and affects 20 million people worldwide. Current treatment options mainly involve biologics that inhibit the vascular endothelial growth factor or complement pathways. However, these treatments have limitations such as high cost, injection-related risks, and limited efficacy. Therefore, new therapeutic targets and strategies have been explored to improve the outcomes of patients with AMD. A promising approach is the use of small-molecule drugs that modulate different factors involved in AMD pathogenesis, such as tyrosine kinases and integrins. Small-molecule drugs offer advantages, such as oral administration, low cost, good penetration, and increased specificity for the treatment of wet and dry AMD. This review summarizes the current status and prospects of small-molecule drugs for the treatment of wet AMD. These advances are expected to support the development of effective and targeted treatments for patients with AMD.


Assuntos
Degeneração Macular , Humanos , Degeneração Macular/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/administração & dosagem , Degeneração Macular Exsudativa/tratamento farmacológico , Desenvolvimento de Medicamentos/métodos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-34909679

RESUMO

Receptor tyrosine kinases (RTKs) have become major targets for anticancer therapy. However, resistance and signaling pathway redundancy has been problematic. The marine-derived apratoxins act complementary to direct kinase inhibitors by downregulating the levels of multiple of these receptors and additionally prevent the secretion of growth factors that act on these receptors by targeting Sec61α, therefore interfering with cotranslational translocation. We have profiled the synthetic, natural product-inspired apratoxin S4 against panels of cancer cells characterized by differential sensitivity to RTK inhibitors due to receptor mutations, oncogenic KRAS mutations, or activation of compensatory pathways. Apratoxin S4 was active at low-nanomolar to sub-nanomolar concentrations against panels of lung, head and neck, bladder, and pancreatic cancer cells, concomitant with the downregulation of levels of several RTKs, including EGFR, MET and others. However, the requisite concentration to inhibit certain receptors varied, suggesting some differential substrate selectivity in cellular settings. This selectivity was most pronounced in breast cancer cells, where apratoxin S4 selectively targeted HER3 over HER2 and showed greater activity against ER+ and triple negative breast cancer cells than HER2+ cancer cells. Depending on the breast cancer subtype, apratoxin S4 differentially downregulated transmembrane protein CDCP1, which is linked to metastasis and invasion in breast cancer and modulates EGFR activity. We followed the fate of CDCP1 through proteomics and found that nonglycosylated CDCP1 associates with chaperone HSP70 and HUWE1 that functions as an E3 ubiquitin ligase and presumably targets CDCP1, as well as potentially other substrates inhibited by apratoxins, for proteasomal degradation. By preventing cotranslational translocation of VEGF and other proangiogenic factors as well as VEGFR2 and other receptors, apratoxins also possess antiangiogenic activity, which was validated in endothelial cells where downregulation of VEGFR2 was observed, extending the therapeutic scope to angiogenic diseases.

12.
Cancers (Basel) ; 13(7)2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33918490

RESUMO

MAPK (mitogen activated protein kinase) and PI3K/AKT (Phosphatidylinositol-3-Kinase and Protein Kinase B) pathways play a key role in melanoma progression and metastasis that are regulated by receptor tyrosine kinases (RTKs). Although RTKs are mutated in a small percentage of melanomas, several receptors were found up regulated/altered in various stages of melanoma initiation, progression, or metastasis. Targeting RTKs remains a significant challenge in melanoma, due to their variable expression across different melanoma stages of progression and among melanoma subtypes that consequently affect response to treatment and disease progression. In this review, we discuss in details the activation mechanism of several key RTKs: type III: c-KIT (mast/stem cell growth factor receptor); type I: EGFR (Epidermal growth factor receptor); type VIII: HGFR (hepatocyte growth factor receptor); type V: VEGFR (Vascular endothelial growth factor), structure variants, the function of their structural domains, and their alteration and its association with melanoma initiation and progression. Furthermore, several RTK inhibitors targeting the same receptor were tested alone or in combination with other therapies, yielding variable responses among different melanoma groups. Here, we classified RTK inhibitors by families and summarized all tested drugs in melanoma indicating the rationale behind the use of these drugs in each melanoma subgroups from preclinical studies to clinical trials with a specific focus on their purpose of treatment, resulted effect, and outcomes.

13.
Cancers (Basel) ; 11(4)2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-31013908

RESUMO

Ovarian carcinoma, the most lethal gynecological cancer, is characterized by late diagnosis, with drug resistance limiting the efficacy of platinum-based therapy. Since some integrins are upregulated in cancer, including ovarian carcinoma, they represent a potential target for drug delivery. Receptor tyrosine kinases are also deregulated in cancer and their expression has been associated with drug resistance. Here, the antitumor effects of three conjugates possessing a selective binder of the extracellular portion of integrin αVß3 covalently linked to the tyrosine kinase inhibitor sunitinib were investigated in cisplatin-sensitive and -resistant ovarian carcinoma cells expressing both tyrosine kinase VEGFR2 and αVß3 at different levels. We found that one of the three compounds was active in inhibiting the growth of both drug-sensitive and -resistant cells in the micromolar range with a slightly increased potency in resistant cells as compared to sunitinib. The same compound markedly impaired cell migratory and invasive abilities and reduced paxillin phosphorylation. Antitumor activity studies in IGROV-1/Pt1 cells xenografted in nude mice revealed a striking activity of this conjugate versus sunitinib. Taken together, our results support the interest of integrin-targeted sunitinib conjugates for the treatment of drug-resistant tumors.

14.
Cancer Lett ; 446: 25-37, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30639534

RESUMO

Drug resistance and off-organ toxicity remain unsolved issues in chemotherapy of advanced-stage melanoma patients. Thus, the creation of new molecular conjugates able to combine a selective accumulation, high ability of internalization and signaling pathway inhibition, are highly requested. Recently, we reported a new class of molecular conjugates, compounds 1-3, where the anti-αVß3 integrin peptidomimetic c(AmpRGD), which is a selective ligand for αVß3 integrin, was covalently bound to the tyrosine kinase inhibitor sunitinib. Here, we report that these c(AmpRGD)-sunitinib conjugates and, in particular, compound 3, are selectively internalized by human melanoma cells through αVß3 receptor-mediated endocytosis. Compound 3 is more effective than sunitinib in reducing in vitro melanoma cells proliferation, cloning efficiency, migration, and invasion. More interestingly, compound 3 is able to significantly reduce the growth of xenografted melanoma tumor developed in immune-compromised mice, more efficiently than an equimolar dose of sunitinib. Indeed, its targeting ability was demonstrated by the selective localization at the tumor level with respect to healthy tissues. Thus, c(AmpRGD)-sunitinib conjugates such as compound 3 could serve as intriguing multiple-target agents to selectively reach melanoma cells and interfere with the progression of the disease.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Melanoma/tratamento farmacológico , Oligopeptídeos/farmacologia , Peptidomiméticos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Sunitinibe/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Feminino , Humanos , Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Células K562 , Masculino , Melanoma/metabolismo , Melanoma/patologia , Camundongos SCID , Terapia de Alvo Molecular , Invasividade Neoplásica , Células PC-3 , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
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
16.
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
17.
Cancers (Basel) ; 10(9)2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30227653

RESUMO

Triple-negative breast cancer (TNBC) is the most challenging subtype to treat due to the lack of estrogen receptor, progesterone receptor, and HER2 expression, which excludes the usage of directed targeted therapy against them. Promising therapeutic targets are the hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR), which expression is frequently elevated in TNBC. Inhibitors of these receptors used as monotherapy are often ineffective. Due to that, we studied the efficacy of combined therapy targeting MET and EGFR simultaneously. Two TNBC cell lines were treated with lapatinib (a dual EGFR and HER2 inhibitor), foretinib (a MET inhibitor), or a combination of the two. After the inhibitors treatment, we verified the cell viability (XTT assay), distribution of the cell cycle phases, the activation of signaling pathways (Western blotting), distribution of invadopodia, fluorescent gelatin digestion (immunofluorescence), and the invasion capacity of cells. A combination of foretinib and lapatinib effectively reduced the viability of examined cells, led to G2/M arrest and reduction of pAKT. There was also a decreasein number of invadopodia formed by cells, their ability to digest gelatin and reduction of cells migration/invasion capacity. Therapy targeting of both EGFR and MET receptors was much more effective against tested cells than monotherapy. We selected a combination of drugs that could be successfully used against this breast cancer subtype.

18.
Eur J Med Chem ; 127: 275-285, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-28068599

RESUMO

Angiogenesis is modulated by a multitude of pro-angiogenic factors including VEGFR-2, Tie-2, and EphB4. Moreover, their crosstalk also had been well elaborated. We have identified several diarylurea-based VEGFR-2 inhibitors as potential anti-angiogenesis agents. As a continuation to our previous research, two series of diaryl malonamide and diaryl thiourea derivatives have been developed as multiplex VEGFR-2/Tie-2/EphB4 inhibitors. Interestingly, the biological evaluation indicated that several compounds bearing trifluoromethyl or trifluoromethoxyl exhibited promising multiplex inhibition against angiogenesis-related VEGFR-2, Tie-2, and EphB4. The representative compound (18a) displayed both potent multi-targeted RTK inhibition and considerable antiproliferative activities against human umbilical vein endothelial cells (EA.hy926). These results will contribute to the discovery of novel muti-targeted anti-angiogenesis agents.


Assuntos
Inibidores da Angiogênese/farmacologia , Desenho de Fármacos , Malonatos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Tioureia/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Malonatos/química , Malonatos/metabolismo , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Receptores Proteína Tirosina Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Tioureia/química , Tioureia/metabolismo
19.
Eur J Med Chem ; 141: 373-385, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29032031

RESUMO

VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti-proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Descoberta de Drogas , Indazóis/farmacologia , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Tioureia/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Indazóis/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Receptores Proteína Tirosina Quinases/metabolismo , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/química
20.
Expert Opin Investig Drugs ; 25(8): 937-56, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27170161

RESUMO

INTRODUCTION: Despite substantial improvements in standards of care, the most common aggressive pediatric and adult high-grade gliomas (HGG) carry uniformly fatal diagnoses due to unique treatment limitations, high recurrence rates and the absence of effective treatments following recurrence. Recent advancements in our understanding of the pathophysiology, genetics and epigenetics as well as mechanisms of immune surveillance during gliomagenesis have created new knowledge to design more effective and target-directed therapies to improve patient outcomes. AREAS COVERED: In this review, the authors discuss the critical genetic, epigenetic and immunologic aberrations found in gliomas that appear rational and promising for therapeutic developments in the presence and future. The current state of the latest therapeutic developments including tumor-specific targeted drug therapies, metabolic targeting, epigenetic modulation and immunotherapy are summarized and suggestions for future directions are offered. Furthermore, they highlight contemporary issues related to the clinical development, such as challenges in clinical trials and toxicities. EXPERT OPINION: The commitment to understanding the process of gliomagenesis has created a catalogue of aberrations that depict multiple mechanisms underlying this disease, many of which are suitable to therapeutic inhibition and are currently tested in clinical trials. Thus, future treatment endeavors will employ multiple treatment modalities that target disparate tumor characteristics personalized to the patient's individual tumor.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Desenho de Fármacos , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Epigênese Genética , Glioma/genética , Glioma/patologia , Humanos , Imunoterapia/métodos , Terapia de Alvo Molecular , Recidiva Local de Neoplasia
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