Inhibitors targeting hepatocyte growth factor receptor and their potential therapeutic applications

Cui, Jingrong Jean

doi:10.1517/13543776.17.9.1035

Cited by 62 publications

(53 citation statements)

References 31 publications

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“…80 The inhibitory activity against C-MET, the cognate receptor for the hepatocyte growth factor, may provide additional synergistic benefit in thyroid carcinomas, given the enhanced expression of the receptor observed in PTC and MTC. [81][82][83] An ongoing phase I dose-escalation study has examined the safety and pharmacokinetics of XL184 in patients with metastatic solid malignancies, with an expansion cohort limited to MTC.…”

Section: Xl184mentioning

confidence: 99%

Targeted therapies for thyroid tumors

Sherman

2011

Modern Pathology

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Systemic chemotherapies for advanced or metastatic thyroid carcinomas have been of only limited effectiveness. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, novel therapies are needed to improve disease outcomes. Multiple novel therapies primarily targeting angiogenesis have entered clinical trials for metastatic thyroid carcinoma. Partial response rates up to 30% have been reported in single-agent studies, but prolonged disease stabilization is more commonly observed. The most successful agents target the vascular endothelial growth factor receptors, with potential targets including the mutant kinases associated with papillary and medullary oncogenesis. Two drugs approved for other malignancies, sorafenib and sunitinib, have had promising preliminary results reported, and are being used selectively for patients who do not qualify for clinical trials. At least one randomized, placebo-controlled phase III trial has been successfully completed, showing improved progression-free survival in patients with advanced or metastatic medullary thyroid carcinoma treated with vandetanib. Randomized trials for other agents are currently underway. Treatment for patients with metastatic or advanced thyroid carcinoma now emphasizes clinical trial opportunities for novel agents with considerable promise. Alternative options now exist for use of tyrosine kinase inhibitors that are well tolerated and may prove worthy of regulatory approval for this disease.

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Section: Xl184mentioning

confidence: 99%

Targeted therapies for thyroid tumors

Sherman

2011

Modern Pathology

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“…XL184 is an oral TKI that effectively blocks VEGFR2 (IC 50 of 0.35 nM), RET (IC 50 of 4 nM) and C-MET (IC 50 of 1.8 nM) (65). A phase I, dose-finding study (66) which enrolled patients with various cancers, including an expansion cohort of 23 medullary thyroid carcinoma, showed some degree of tumor shrinkage in almost all patients of the latter group with 55% (12/22 patients with ≥ 3 months of follow-up) qualifying for partial responders according to RECIST criteria.…”

Section: Xl184mentioning

confidence: 99%

Targeted molecular therapies in thyroid carcinoma

Romagnoli

Moretti

Voce

et al. 2009

Arq Bras Endocrinol Metab

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Thyroid cancer incidence has significantly increased in the last three decades and many patients seek medical attention for its treatment every year. Among follicular cell-derived tumors, the majority are differentiated thyroid carcinomas (DTC), whose prognosis is very good with only 15% of the cases presenting disease persistence or recurrence after initial treatment. Medullary thyroid carcinoma has a worse prognosis, especially in patients with diffused cancers at the time of initial surgery. Traditional treatment options for persistent or recurrent disease include additional surgery, radioiodine treatment and TSH-suppression in DTC patients; external beam radiotherapy, and cytotoxic chemotherapy, often have low efficacy and many patients with advanced disease ultimately die. In the last two decades many of the molecular events involved in cancer formation have been uncovered. This knowledge has prompted the development of novel therapeutic strategies mainly based on the inhibition of key molecular mediators of the tumorigenic process. In particular the class of small-molecule tyrosine kinase inhibitors was enriched by many compounds that have reached clinical trials and in some cases have had approval for clinical use in specific cancers. Many of these compounds entered clinical trials also for locally advanced or metastatic thyroid carcinomas showing very promising results. Arq Bras Endocrinol Metab. 2009;53(9):1061-73 Keywords Thyroid carcinoma; radioiodine therapy; external beam radiation therapy; cytotoxic chemotherapy; targeted therapies; tyrosine kinase inhibitors ReSumo O câncer de tireoide tem aumentado significativamente nas últimas três décadas e muitos pacientes têm buscado cuidados médicos para o tratamento a cada ano. Entre os tumores derivados de células foliculares, a maioria é carcinoma diferenciado de tireoide (CDT), cujo prognóstico é muito bom, em que somente em 15% dos casos a doença é persistente ou recorrente após o tratamento inicial. O carcinoma medular de tireoide tem um prognóstico pior, especialmente em pacientes com câncer difuso no momento da cirurgia inicial. As opções no tratamento tradicional para a doença persistente ou recorrente incluem cirurgia adicional, radioiodoterapia e supressão de TSH em pacientes CDT; a radioterapia externa e a quimioterapia citotóxica apresentam com frequência uma baixa eficácia e muitos pacientes com doença avançada não sobrevivem. Nas últimas duas décadas, muitos dos eventos envolvidos na formação do câncer tornaram-se conhecidos. Esse conhecimento possibilitou o desenvolvimento de novas estratégias terapêuticas, baseadas principalmente na inibição de mediador molecularchave no processo tumorigênico. Em particular, a classe das pequenas moléculas inibidoras de tirosina-quinase foi enriquecida por muitos compostos investigados em estudos clínicos e alguns casos foram aprovados para uso clínico em tipos específicos de câncer. Muitos desses compostos foram aplicados em estudos clínicos de câncer de tireoide com extensa invasão local ou metást...

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“…Since c-Met is at the crossing of many roads leading to tumorigenesis and metastasis, targeting this receptor could be a relatively simple way to interfere with many pathways simultaneously (Corso et al, 2005). Various strategies are currently in development to disrupt the HGF-Met signal transduction pathway, in which small molecular inhibitors have been a particularly active field (Underiner et al, 2010;Cui, 2007;Cui et al, 2012;Furlan et al, 2012;Colombo et al, 2012). In our previous study, we discovered some novel c-Met inhibitors using Pfizer's 3H-[1,2,3]triazolo[4,5-b] pyrazine derivative PF-04217903 and Janssen' s 3H-[1,2,4]-triazolo [4,3-b] pyridazine derivative JNJ-38877605 as leading compounds (Figs.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and molecular docking analysis of some novel 7-[(quinolin-6-yl)methyl] purines as potential c-Met inhibitors

Jiebo

et al. 2015

Med Chem Res

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HGF/c-Met signaling pathway has come into the spotlight as a promising therapeutic target for inhibiting tumor growth and has become one of the leading molecular targets in cancer. Various strategies are currently in development to disrupt the HGF-Met signal transduction pathway, in which small molecular inhibitors have been a particularly active field. On the basis of the structures of two c-Met inhibitors, PF-04217903 and JNJ-38877605, some novel 7-[(quinolin-6-yl)methyl] purines (4a-4e) were rationally designed on the principle of bioisosterism strategy. These compounds were synthesized and evaluated as novel c-Met inhibitors. Molecular docking experiments analyzed the results and explained the molecular mechanism of eminent activities to c-Met. The results showed that all the title compounds were active against c-Met enzyme to some extent. Though these compounds did not demonstrate inhibition as we expected, this study provided important information for building diversification of chemical library and molecular docking experiment supplied the basis for further research works. Graphical Abstract Some novel7-[(quinolin-6-yl)methyl] purines as potential c-Met inhibitors have been designed and prepared. Their synthesis and spectral characterization are reported here.

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Inhibitors targeting hepatocyte growth factor receptor and their potential therapeutic applications

Cited by 62 publications

References 31 publications

Targeted therapies for thyroid tumors

Targeted therapies for thyroid tumors

Targeted molecular therapies in thyroid carcinoma

Design, synthesis and molecular docking analysis of some novel 7-[(quinolin-6-yl)methyl] purines as potential c-Met inhibitors

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