Current opinion in investigational drugs最新文献_第2页

STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. STA-9090是一种小分子热休克蛋白90抑制剂，具有治疗癌症的潜力。

Current opinion in investigational drugs Pub Date : 2010-12-01

Yisong Wang, Jane B Trepel, Leonard M Neckers, Giuseppe Giaccone

{"title":"STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer.","authors":"Yisong Wang, Jane B Trepel, Leonard M Neckers, Giuseppe Giaccone","doi":"","DOIUrl":"","url":null,"abstract":"STA-9090 is a second-generation Hsp90 inhibitor in clinical development by Synta Pharmaceuticals for the intravenous treatment of hematological and solid malignancies. It is a resorcinol-containing triazole compound, with a novel chemical structure that is unrelated to the geldanamycin class of Hsp90 inhibitors. STA-9090 binds to the ATP-binding domain at the N-terminus of Hsp90 and acts as a potent Hsp90 inhibitor by inducing degradation of multiple oncogenic Hsp90 client proteins including HER2/neu, mutated EGFR, Akt, c-Kit, IGF-1R, PDGFRα, Jak1, Jak2, STAT3, STAT5, HIF-1α, CDC2, c-Met, and Wilms' tumor 1. STA-9090, at low nanomolar concentrations, potently arrested cell proliferation and induced apoptosis in a wide variety of human cancer cell lines, including many receptor tyrosine kinase inhibitor- and tanespimycin-resistant cell lines. Moreover, administration of STA-9090 led to significant tumor shrinkage in several tumor xenograft models in mice and appeared to be less toxic. Furthermore STA-9090 demonstrated better tumor penetration compared with tanespimycin. In initial phase I clinical trials, STA-9090 was well tolerated and has demonstrated activity. The further development of this agent, and the other Hsp90 inhibitors, may be dependent on the tumor type and the primary oncogenic driving forces.","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":" ","pages":"1466-76"},"PeriodicalIF":0.0,"publicationDate":"2010-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29533177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia. Bafetinib，一种双重Bcr-Abl/Lyn酪氨酸激酶抑制剂，用于治疗白血病。

Current opinion in investigational drugs Pub Date : 2010-12-01

Fabio P S Santos, Hagop Kantarjian, Jorge Cortes, Alfonso Quintas-Cardama

{"title":"Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia.","authors":"Fabio P S Santos, Hagop Kantarjian, Jorge Cortes, Alfonso Quintas-Cardama","doi":"","DOIUrl":"","url":null,"abstract":"Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. Besides Abl, bafetinib targets the Src family kinase Lyn, which has been associated with resistance to imatinib in CML. In preclinical studies, bafetinib was 25- to 55-fold more potent than imatinib in vitro and ≥ 10-fold more potent in vivo. Bafetinib inhibits 12 of the 13 most frequent imatinib-resistant Bcr-Abl point mutations, but not a Thr315Ile mutation. A small fraction of bafetinib crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Data from a phase I clinical trial conducted in patients with imatinib-resistant or -intolerant CML have confirmed that bafetinib has clinical activity in this setting, inducing a major cytogenetic response in 19% of those patients in chronic phase. Currently, bafetinib is being developed in two phase II clinical trials for patients with B-cell chronic lymphocytic leukemia and prostate cancer, and a trial is in progress for patients with brain tumors.","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 12","pages":"1450-65"},"PeriodicalIF":0.0,"publicationDate":"2010-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10593129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

EC-145, a folate-targeted Vinca alkaloid conjugate for the potential treatment of folate receptor-expressing cancers. EC-145，叶酸靶向长春花生物碱偶联物，用于叶酸受体表达癌症的潜在治疗。

Current opinion in investigational drugs Pub Date : 2010-12-01

Franco Dosio, Paola Milla, Luigi Cattel

{"title":"EC-145, a folate-targeted Vinca alkaloid conjugate for the potential treatment of folate receptor-expressing cancers.","authors":"Franco Dosio, Paola Milla, Luigi Cattel","doi":"","DOIUrl":"","url":null,"abstract":"EC-145, under development by Endocyte, is a conjugate composed of desacetylvinblastine monohydrazide linked through a peptide spacer to the targeting moiety folic acid, for the potential intravenous treatment of folate receptor-overexpressing tumors, in particular ovarian and lung cancers. In vitro studies demonstrated that EC-145 selectively binds to cells that overexpress the folate receptor, causing dose-dependent cytotoxicity. Furthermore, coincubation of the KB human nasopharyngeal carcinoma cell line with EC-145 and doxorubicin resulted in synergistic antitumor activity. Experiments in mouse tumor xenograft models have confirmed the potency of EC-145 and the curative effects of the drug conjugate were demonstrated in an aggressive lymphoma xenograft model. In a phase I clinical trial in patients with advanced or metastatic solid tumors, adverse events were generally of moderate severity with the most frequent being fatigue, constipation and peripheral sensory neuropathy. Preliminary data from a phase II clinical trial in patients with advanced ovarian cancer demonstrated that third- or fourth-line treatment with EC-145 yielded better disease control than second- or third-line liposomal doxorubicin. Coadministration of EC-145 and liposomal doxorubicin produced a statistically significant increase in progression-free survival over standard therapy in patients with platinum-resistant ovarian cancer. Phase III clinical trials are expected to confirm these promising results.","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":" ","pages":"1424-33"},"PeriodicalIF":0.0,"publicationDate":"2010-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29532723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AT-9283, a small-molecule multi-targeted kinase inhibitor for the potential treatment of cancer. AT-9283是一种小分子多靶点激酶抑制剂，具有治疗癌症的潜力。

Current opinion in investigational drugs Pub Date : 2010-12-01

Shinya Kimura

引用次数: 0

Reporting disease control rates or clinical benefit rates in early clinical trials of anticancer agents: useful endpoint or hype? 在抗癌药物的早期临床试验中报告疾病控制率或临床获益率:有用的终点还是炒作?

Current opinion in investigational drugs Pub Date : 2010-12-01

Mario Sznol

{"title":"Reporting disease control rates or clinical benefit rates in early clinical trials of anticancer agents: useful endpoint or hype?","authors":"Mario Sznol","doi":"","DOIUrl":"","url":null,"abstract":"Disease Control Rate (DCR) and Clinical Benefit Rate (CBR) are defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents. DCR and CBR are commonly reported in many clinical trials in abstracts, papers, meeting presentations and media releases. The frequent use of these measures of drug activity presents the question of whether DCR and CBR are useful additional endpoints in early clinical trials, and if they can reasonably predict the success of an agent in subsequent, adequately powered, randomized trials. There are no comprehensive analyses to demonstrate that CBR and DCR add to the value of traditional response/activity endpoints in early clinical trials. Data from phase II clinical trials in which the DCR or CBR are reported suggest that DCR or CBR provides ambiguous information that likely exaggerates the anticancer activity of the therapy. The terms 'disease control' and 'clinical benefit' in the context of non-randomized trials are themselves disingenuous because neither tumor regression nor stable disease, defined without any consideration of duration of effect or reduction of symptoms appropriate for the specific patient population, are evidence of these endpoints in an individual patient.","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":" ","pages":"1340-1"},"PeriodicalIF":0.0,"publicationDate":"2010-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29627808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Function of NOD-like receptors in immunity and disease. nod样受体在免疫和疾病中的作用。

Current opinion in investigational drugs Pub Date : 2010-11-01

Maryse Dagenais, Jeremy Dupaul-Chicoine, Maya Saleh

引用次数: 0

Novel treatments for systemic lupus erythematosus. 系统性红斑狼疮的新疗法。

Current opinion in investigational drugs Pub Date : 2010-11-01

Mary Gayed, Caroline Gordon

{"title":"Novel treatments for systemic lupus erythematosus.","authors":"Mary Gayed, Caroline Gordon","doi":"","DOIUrl":"","url":null,"abstract":"Systemic lupus erythematosus (SLE) is an autoimmune disease that is associated with the production of autoantibodies, and with considerable morbidity and mortality. There has been much interest in developing more specific therapies for this disease, which is currently managed with immunosuppressive drugs, predominantly corticosteroids, azathioprine, methotrexate and cyclophosphamide, in combination with hydroxychloroquine. Mycophenolate mofetil has been demonstrated to be as efficacious as cyclophosphamide in patients with lupus nephritis, and is being used increasingly in the clinic despite not being licensed for this indication. Novel methods of reducing autoantibody formation in SLE include the use of mAbs that modulate and/or deplete B-cells (anti-CD22 and anti-CD20 antibodies, respectively), or that interfere with the stimulatory effects of the soluble factor B-lymphocyte stimulator (anti-BLys antibodies). Alternative approaches include the use of atacicept (Merck Serono), a transmembrane activator and calcium modulator ligand interactor (TACI)-Ig fusion protein, which inhibits B-cell stimulation by binding to BLys and a profileration-inducing ligand (APRIL), or toleragens such as abetimus. Blocking costimulatory molecule interactions, such as the CD40-CD40 ligand interaction with mAbs and the CD28-B7 interaction with a soluble cytotoxic T-lymphocyte antigen 4 (CTLA-4)-IgG1 construct (abatacept), has also been attempted as a therapeutic strategy for SLE. The most promising strategy for a new drug for SLE is belimumab (Human Genome Sciences/GlaxoSmithKline), an anti-BLys antibody, as two phase III clinical trials with this drug recently met their primary endpoints. In this review, these novel approaches to the treatment of SLE, including the potential of targeting cytokine pathways involved in autoimmunity, are discussed.","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 11","pages":"1256-64"},"PeriodicalIF":0.0,"publicationDate":"2010-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29535263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Resetting autoimmunity in the nervous system: The role of hematopoietic stem cell transplantation. 重置自身免疫在神经系统:造血干细胞移植的作用。

Current opinion in investigational drugs Pub Date : 2010-11-01

Paolo A Muraro, Sofia V Abrahamsson

引用次数: 0

Vedolizumab, a humanized mAb against the α4β7 integrin for the potential treatment of ulcerative colitis and Crohn's disease. Vedolizumab是一种针对α4β7整合素的人源化单抗，可用于治疗溃疡性结肠炎和克罗恩病。

Current opinion in investigational drugs Pub Date : 2010-11-01

Herbert Tilg, Arthur Kaser

{"title":"Vedolizumab, a humanized mAb against the α4β7 integrin for the potential treatment of ulcerative colitis and Crohn's disease.","authors":"Herbert Tilg, Arthur Kaser","doi":"","DOIUrl":"","url":null,"abstract":"Advances in immunology and genetics have identified new therapeutic targets to control inflammation and symptoms in patients with inflammatory bowel diseases (IBD). Despite the success of anti-TNF therapies in the treatment of IBD, a considerable proportion of patients are refractory to treatment, highlighting an unmet medical need for new therapies. Molecules that direct the trafficking of inflammatory cells, such as the α4β7 integrin, are attractive targets for new drug candidates. The α4β7 integrin is involved in lymphocyte recruitment to the normal and inflamed gut mucosa, and the lymphoid tissue. The pan-α4 integrin neutralizing mAb, natalizumab, is not gut-selective but has demonstrated efficacy in IBD. However, treatment was associated with the occurrence of progressive multifocal leukoencephalopathy, which has limited its use, especially in Europe. Vedolizumab (MNL-0002), Millennium Pharmaceutical's gut-specific, α4β7 integrin-neutralizing mAb, does not affect peripheral blood cell counts and appears to lack systemic effects. Data from phase II clinical trials of vedolizumab demonstrated efficacy with an attractive safety profile, especially in ulcerative colitis. Large phase III, multicenter trials in both ulcerative colitis and Crohn's disease will provide valuable data for the ongoing development of vedolizumab, which might evolve as a new anti-inflammatory treatment option for the management of therapy-refractory patients.","PeriodicalId":10978,"journal":{"name":"Current opinion in investigational drugs","volume":"11 11","pages":"1295-304"},"PeriodicalIF":0.0,"publicationDate":"2010-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29535267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Muscarinic receptors as targets for anti-inflammatory therapy. 毒蕈碱受体作为抗炎治疗的靶点。

Current opinion in investigational drugs Pub Date : 2010-11-01

María Elena Sales

引用次数: 0