A Phase 1, Multicenter, Open-Label, Dose Escalation Study of Tandutinib (Formerly MLN518) in Combination With Temozolomide and Bevacizumab Following Concurrent Radiation Therapy and Temozolomide in the Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme.

This is a safety study of tandutinib in combination with temozolomide and bevacizumab after people have received radiation therapy and temozolomide treatment. This study will determine the maximum safe dose of tandutinib when combined with temozolomide and bevacizumab and evaluate the safety of the combination treatment.

开始日期2009-06-01

申办/合作机构

Millennium Pharmaceuticals, Inc.

NCT00667394

/ Completed临床2期IIT

A Phase 2 Trial of Tandutinib in Combination With Bevacizumab for Patients With Recurrent High-Grade Gliomas

Background:
In order to survive, brain tumors must have a network of blood vessels to supply it with oxygen and nutrients. The tumors produce substances that enable new blood vessels to form.
Tandutinib and Bevacizumab are experimental drugs that may prevent new blood vessel formation and thereby slow or stop tumor growth in the brain.
Objectives:
To determine the safety and side effects of Tandutinib in combination with Bevacizumab in patients with brain tumors.
To evaluate the response of brain tumors to treatment with Tandutinib and Bevacizumab.
Eligibility:
Patients 18 years of age and older with a malignant brain tumor for whom standard treatments (surgery, radiation and chemotherapy) are no longer effective.
Design:
Patients receive treatment in 4-week cycles as follows: Tandutinib by mouth twice a day every day and intravenous (through a vein) infusions of Bevacizumab over 90 minutes (or less if well tolerated) every 2 weeks. Treatment may continue for up to 1 year, and possibly longer, as long as there are no signs of tumor growth or serious treatment side effects.
Patients are evaluated with magnetic resonance imaging (MRI), computed tomography (CT) and positron emission tomography (PET) scans before starting treatment and then periodically to determine the response to treatment.
Patients have physical and neurological examinations every 4 weeks and blood tests every 2 weeks. They complete quality of life questionnaires every 4 weeks.

开始日期2008-04-01

申办/合作机构

National Cancer Institute

NCT00379080

/ Completed临床1/2期IIT

A Feasibility Assessment and a Phase I/II Trial of MLN518 for Treatment of Patients With Recurrent Glioblastoma

This phase I/II trial is studying the side effects and best dose of tandutinib and to see how well it works in treating patients with recurrent or progressive glioblastoma.Tandutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

开始日期2007-01-01

申办/合作机构

National Cancer Institute

100 项与坦度替尼相关的临床结果

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100 项与坦度替尼相关的转化医学

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100 项与坦度替尼相关的专利（医药）

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134

项与坦度替尼相关的文献（医药）

2025-01-01·JOURNAL OF INVESTIGATIVE DERMATOLOGY

Identifying Potential Drug Targets for Keloid: A Mendelian Randomization Study

Article

作者: Yuan, Zhaoqi ; Wang, Xiuxia ; Liu, Fei ; Yang, Jun ; Luo, Xusong ; Wang, Yinmin

Keloids are a skin fibrosis disease characterized by troublesome symptoms, a varying degree of recurrence and inevitable side effects from treatments. Thus, identifying their drug targets is necessary. A 2-sample Mendelian randomization analysis was conducted using proteins from the intersection of the deCODE database and "The Druggable Genome and Support for Target Identification and Validation in Drug Development" as the exposure variable. The outcome variable was based on recently published GWAS of keloids. Summary data-based Mendelian randomization and colocalization analysis was employed to distinguish pleiotropy from linkage. Candidate targets underwent drug target analysis. The primary findings were validated through single-cell RNA-sequencing data, Western Blot and immunofluorescence staining on keloids. Seven proteins were identified as potential drug targets for keloids. Among these proteins, Hedgehog-interacting protein, neurotrimin [NTM], KLKB1, and CRIPTO showed positive correlations with keloids, while PLXNC1, SCG3 and PDGFD exhibited negative correlations. Combined with the single-cell RNA-sequencing data, NTM, PLXNC1, and PDGFD were found highly expressed in the fibroblasts. NTM showed a significant increase in keloids as compared to normal scars. In accordance with the analysis, higher levels of protein expression of NTM in keloids compared to normal skin was observed. The identified proteins may be appealing drug targets for keloids treatment with a special emphasis on NTM.

2025-01-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Identification of inhibitors targeting the FLT3-ITD mutation through 4D-QSAR, in vitro, and in silico

Article

作者: Yan, Hong ; Zhong, Qidi ; Chu, Dongchen ; Zhang, Xiaokun ; Zhang, Yu ; Ji, CuiCui ; Wei, Chaochun ; Wang, Juan

The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation is a key target for acute myeloid leukemia (AML) treatment. The second-generation inhibitors such as Gilteritinib still present off-target effects and associated side effects. Therefore, identifying novel FLT3-ITD inhibitors has become a promising strategy for AML treatment. In this study, a 4D-QSAR model was developed based on Gilteritinib and its analogues, and it was found that introducing hydrophobic bulky groups at the piperazine or piperidine of Gilteritinib would enhance the binding affinity to FLT3-ITD. So, three series of targeted compounds (A1-A5, B1-B5 and C1-C5) were designed and synthesized. The antiproliferative activity against MOLM-13 cells was evaluated in vitro. Compound A1 (IC₅₀ = 25.65 nM), with a cubane group at the piperazine position; Compounds B2 (IC₅₀ = 63.38 nM) and C2 (IC₅₀ = 54.96 nM), with a norbornene group at the piperidine position, showed the strongest inhibition in their series. Their IC₅₀ values were comparable to that of the positive control Gilteritinib (IC₅₀ = 22.37 nM). FLT3-ITD was confirmed as the degradation target through a kinase inhibition assay, where the IC₅₀ values were 2.12 nM (Compound A1), 1.29 nM (Compound B2), and 3.06 nM (Compound C2), which were comparable to that of Gilteritinib (IC₅₀ = 0.43 nM). Additionally, molecular docking and molecular dynamics (MD) simulations showed that Compounds A1, B2, and C2 had similar binding modes to that of Gilteritinib with more stable affinities. Overall, these results demonstrated that Compounds A1, B2, and C2 were promising inhibitors for targeting AML with FLT3-ITD mutation.

2023-07-18·Journal of molecular modeling

Identification of potential RapJ hits as sporulation pathway inducer candidates in Bacillus coagulans via structure-based virtual screening and molecular dynamics simulation studies.

Article

作者: Nezafat, Navid ; Irajie, Cambyz ; Mirmajidi, Seyedeh Habibeh ; Ghasemi, Younes ; Savardashtaki, Amir ; Negahdaripour, Manica

BACKGROUND:

The bacterium Bacillus coagulans has attracted interest because of its ability to produce spores and advantageous probiotic traits, such as facilitating food digestion in the intestine, managing some disorders, and controlling the symbiotic microbiota. Spore-forming probiotic bacteria are especially important in the probiotic industry compared to non-spore-forming bacteria due to their stability during production and high resistance to adverse factors such as stomach acid. When spore-forming bacteria are exposed to environmental stresses, they enter the sporulation pathway to survive. This pathway is activated by the final phosphorylation of the master regulator of spore response, Spo0A, and upon achieving the phosphorylation threshold. Spo0A is indirectly inhibited by some enzymes of the aspartate response regulator phosphatase (Rap) family, such as RapJ. RapJ is one of the most important Rap enzymes in the sporogenesis pathway, which is naturally inhibited by the pentapeptides.

METHODS:

This study used structure-based virtual screening and molecular dynamics (MD) simulation studies to find potential RapJ hits that could induce the sporulation pathway. The crystal structures of RapJ complexed with pentapeptide clearly elucidated their interactions with the enzyme active site.

RESULTS:

Based on the binding compartment, through molecular docking, MD simulation, hydrogen bonds, and binding-free energy calculations, a series of novel hits against RapJ named tandutinib, infigratinib, sitravatinib, linifanib, epertinib, surufatinib, and acarbose were identified. Among these compounds, acarbose obtained the highest score, especially in terms of the number of hydrogen bonds, which plays a major role in stabilizing RapJ-ligand complexes, and also according to the occupancy percentages of hydrogen bonds, its hydrogen bonds were more stable during the simulation time. Consequently, acarbose is probably the most suitable hit for RapJ enzyme. Notably, experimental validation is crucial to confirm the effectiveness of the selected ligands.

项与坦度替尼相关的新闻（医药）

2023-07-17

·智慧芽新药科讯

报告下载｜FLT3抑制剂的管线及专利调研报告

2023年7月17日，智慧芽新药情报库正式发布最新管线及专利调研报告《FLT3抑制剂的管线及专利调研报告》（以下简称“报告”）。报告共分为靶点简介、管线药物、专利分析、总结四部分。在“管线药物”部分，先对“全球管线药物概况’进行了统计，包括靶点、适应症、药物类型、临床试验的国家/地区、研发进度五方面的分布特点，并汇总了在中国开展研究的FLT3靶向药物信息，最后解析了已上市的9款靶向药物。在”专利分析“部分，先统计了全球专利分布特点，后对Top 1 专利申请机构Novartis AG的专利进行了较为详细的分析。报告全文限时免费阅读下载，了解详情请点击下方图片。一、靶点简介1.1 FLT3的结构与表达FMS样酪氨酸激酶3（FMS-like tyrosine kinase 3，FLT3）广泛表达于造血干细胞和祖细胞中（图1），是由原癌基因FLT3编码的跨膜蛋白。它属于III型受体酪氨酸激酶（receptor tyrosine kinase，RTK）家族，该家族还包括PDGFR、FMS和KIT。图1 FLT3在正常造血中的表达。图中显示了正常造血过程中细胞的成熟和分化。“+，–，+/–或？（未知）”表明FLT3的表达与该过程的关联。如图2，FLT3基因转录产生FLT3 mRNA，之后再翻译成FLT3蛋白。FLT3包含五个细胞外免疫球蛋白样结构域（extracellular immunoglobulin-like domain，E），一个跨膜结构域（transmembrane domain，TM），一个近膜结构域（juxtamembrane domain，JM）和两个酪氨酸激酶结构域（tyrosine-kinase domain，K）。细胞质的FLT3通过糖基化（G）促使受体向细胞膜上定位。图2 野生型FLT3的结构和活化1.2 FLT3的活化与功能配体：造血系统中的许多细胞都可以产生FLT3配体（FLT3L），除大脑等少数组织中没有明显的FLT3L表达外，多个组织，包括造血器官（如脾脏、胸腺、外周血和骨髓）、前列腺、卵巢、肾脏、肺、结肠、小肠、睾丸、心脏和胎盘均有表达，其中外周血单核细胞的表达水平最高，这与FLT3的有限表达形成了鲜明对比。FLT3 通过与配体结合而被激活，导致其二聚化和构象变化。随后FLT3 自身磷酸化（phosphorylation，P）并触发信号传导，激活细胞内信号级联，例如PI3K/AKT/mTOR、RAS/RAF/MAPK和JAK/STAT, 诱导细胞的增殖、分化、存活和凋亡。二聚化后的FLT3受体迅速内化和降解（图2）。FLT3在正常细胞中的功能：FLT3L激活FLT3促进早期祖细胞的体外生长。FLT3介导的反应高度依赖于细胞类型和其他生长因子。Gabbianelli等人发现，用FLT3L刺激而不添加其他生长因子可促进早期造血祖细胞的单核细胞分化，而没有明显的促增殖反应。然而，FLT3L刺激与其他生长因子（如白细胞介素-3、G-CSF、CSF1、GM-CSF、促红细胞生成素和KIT配体）结合会产生更强烈的增殖反应，并大大增强粒细胞-单核细胞集落形成单位的发育。1.3 FLT3的突变与致病机制FLT3突变在一些急性淋巴细胞白血病（ALL，1-3%）、骨髓异常增生（MDS，5-10%）患者中被发现；是急性髓系白血病（acute myeloid Leukaemia，AML）最常见的遗传病变，约占AML患者总数的30%-40%。这使FLT3成为血液系统恶性肿瘤中最常见的突变基因之一。FLT3 最常见的突变有两种，分别是内部串联重复(internal tandem duplication，ITD)和细胞内酪氨酸激酶结构域(TKD)突变。如图3，ITD突变发生在JM区域，占AML患者的15-35%；TKD点突变发生在K区域（占AML患者的5-10%），与其他RTK（例如KIT 和FMS）中出现的点突变同源。图3 FLT3 突变的结构和位置正常情况下，在没有配体（L）时，膜表面受体大多保持失活的单体形式。单体受体的构象可能具有阻止二聚化的排斥力，并可能阻止衔接蛋白（adaptor protein，绿色）对接（图4-a)。与配体结合后，FLT3的构象发生变化，促进二聚化、磷酸化（P）和与衔接蛋白的对接，将信号传递给下游效应蛋白（图4-b，蓝色箭头）。FLT3-ITDs可能通过改变所表达受体的构象来促进FLT3在不与配体结合的情况下，自我驱动二聚化和活化。实验表明，如图4-c，与野生型FLT3相比，含有ITD的FLT3可能激活普通（蓝色）和独特（红色）的两种途径。与ITD相关的构象变化可能会改变受体的结构，使得可以与独特的衔接蛋白直接对接。TKD2中的misense突变也可能促进配体依赖性激活（图4-d）。图4 野生型和突变型FLT3激活模式的比较二、管线药物2.1 全球FLT3管线药物靶点及适应症分布第一代FLT3抑制剂，包括sorafenib, sunitinib, midostaurin, tandutinib, 和lestaurtinib等，是具有抗 FLT3 活性的多靶点抑制剂，它们对 FLT3 没有特异性，并且对其他各种RTK（如 PDGFR、KIT、VEGFR、RAF 或 JAK2）具有抑制作用。据统计（图5），当前多靶点抑制剂主要包括FLT3+AXL（5款）、 FLT3 + JAK2 （2款）、 CSF-1R + FLT3 + c-Kit （2款）、BRAF + CRAF + FLT3 + PDGFRβ + RET + VEGFR1 + VEGFR2 + VEGFR3 + c-Kit （2款）等。由于 RATIFY 试验的积极结果， midostaurin+化疗已被 FDA 和 EMA 批准用于一线治疗FLT3突变的AML。但大多数情况下，这些抑制剂作为 AML 单一疗法，其临床疗效并不理想，而且它们的脱靶效应也增加了不良事件的发生风险。因此，除sorafenib, midostaurin等少数药物外，第一代用于AML单一治疗的FLT3抑制剂大多已停止研究。图5 排名前十的靶点及其药物所属研发阶段的分布第二代 FLT3抑制剂，通过合理的药物设计开发，更有效、更具特异性，并且与脱靶效应相关的毒性更小，成为当前精准治疗的研究主流。在当前132款具有FLT3抑制活性的靶向药物中有44款为FLT3单靶点抑制剂，占总管线药物的33.3%(图5)。Gilteritinib是第一个获批的第二代FLT3抑制剂，也是第一个用于AML单药治疗的有效FLT3抑制剂。此外值得注意的是，不是所有的FLT3抑制剂都布局AML，一些多靶点抑制剂，如pexidartinib (Turalio)在临床上并未用于AML 治疗，而是被批准用于治疗成人腱鞘巨细胞瘤(TGCT)患者。据统计（图6），除AML外，非小细胞肺癌、急性淋巴细胞白血病等也是FLT3抑制剂的重要开发领域。图6 排名前十的适应症及其药物所属研发阶段的分布（本章节的药物类型、临床试验、研发进度、国内管线信息汇总、上市药物解析等请详见报告）三、专利分析3.1 全球BCMA相关专利分布特点的统计结果在智慧芽新药情报库→“专利检索”板块→“靶点”栏，输入关键词“FLT3”，检索后共得到16,091条医药类专利信息，现基于这些信息对全球专利的申请/授权趋势、简单法律状态、国家/地区、治疗领域进行统计。申请/授权趋势：图7，从申请时间维度分析，从2005年到2020年，专利申请数呈逐年增加的趋势，其中2020年达到了1432个申请。然而，从2020年到2023年，专利申请数急剧下降，仅有69个申请。这种趋势可能是由于多个因素导致的，例如行业竞争加剧、技术进步放缓等。（对简单法律状态、国家/地区分布、治疗领域分布的统计请见报告）图7 近20年专利申请/授权趋势（如果2012年专利申请在2014年获得授权，授予的专利将在2012年专利申请中以绿色显示）3.2 Top 1 专利申请机构Novartis AG的专利分析据统计，Novartis AG是专利申请最多的机构，涉及938项，也是与其他机构合作申请专利最多的机构，共有208项。其次是Gilead Sciences, Inc.和Dana-Farber Cancer Institute, Inc.，分别有71和39个合作申请（图8）。这些合作关系反映了不同机构之间在药物研发方面的合作和共享资源的趋势。图8 Top 10 专利申请机构合作概况申请量最高的Novartis AG除独立申请七百多项专利外，另有二百多项与其他机构合作。近20年的专利申请出现两个高峰（图9），2006年为第一个高峰，共有66项申请，第二个高峰出现在2020年，有94项。授权高峰出现在2016年，有32项。图9 Novartis近10年BMCA相关专利申请/授权趋势（统计逻辑与图7一致）（Novartis公司FLT3靶向药的核心专利信息汇总及分析，请详见报告）由于报告中插入的各类药物、机构等链接，在PC端的“在线阅读”状态下可直接实现跳转，体验更加，建议将PC端的阅读方式作为首选。点击图片，直达获取报告全文 👇👇👇 版权声明：本报告版权由智慧芽所有，未经智慧芽授权不得转载、摘编或利用其它方式使用。已获授权的应在授权范围内使用，并注明来源，违反上述声明者，智慧芽将追究其相关法律责任。授权相关事宜请联系：phs@patsnap.com

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100 项与坦度替尼相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
急性早幼粒细胞白血病	临床2期	-	Millennium Pharmaceuticals, Inc.	2006-03-01
胶质母细胞瘤	临床2期	美国	Millennium Biotechnologies, Inc.	-
肾细胞癌	临床2期	-	Takeda Pharmaceutical Co., Ltd.	-
多形性胶质母细胞瘤	临床1期	-	Millennium Pharmaceuticals, Inc.	2009-06-01
骨髓增生异常综合征	临床1期	美国	Millennium Pharmaceuticals, Inc.	2002-05-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00667394 (Pubmed)	临床2期	复发性胶质母细胞瘤	41	Tandutinib 500 mg b.i.d. + Bevacizumab 10 mg/kg every 2 weeks	築齋膚糧鑰積獵築衊齋(壓繭簾鏇衊艱壓鬱顧積) = Four of six with grade ≥3 tandutinib-related myasthenic-like muscle weakness had electromyography-proven neuromuscular junction pathology 襯糧築獵淵網願餘願壓 (範積衊窪窪觸範壓鏇觸 )	积极	2016-01-01
NCT00408902 (CTgov)	临床2期	转移性透明细胞性肾细胞癌	10	laboratory biomarker analysis+tandutinib	築鑰鏇鑰鑰獵簾築顧鑰 = 壓餘齋壓積夢築繭積積醖範遞簾襯構製廠鬱齋 (淵壓艱製夢鹽壓醖積糧, 構鑰憲壓鑰顧糧艱襯艱 ~ 簾觸鏇衊網蓋築艱繭顧) 更多	-	2015-02-04
NCT00390468 (Pubmed \| Cancer Chemother Pharmacol)	临床2期	骨转移癌	18	Tandutinib 500 mg	艱餘築糧網淵廠築遞鏇(醖獵鹽鑰膚蓋醖鏇願遞) = 繭糧網鑰糧獵鏇膚廠壓憲艱廠淵範觸鹹窪觸遞 (製膚衊窪網繭窪顧鬱蓋 )	-	2011-10-01
NCT00390468 (CTgov)	临床2期	疼痛 \| 去势抵抗性前列腺癌 \| 骨转移癌	18	Tandutinib	觸網廠齋襯範選廠餘蓋 = 顧齋遞襯襯衊積繭蓋襯壓廠齋製餘鬱繭獵網築 (壓觸繭窪衊鏇夢膚範糧, 鑰糧網範願觸夢積獵壓 ~ 網繭顧醖衊構選網築鹹) 更多	-	2011-06-07