(XL-228) - 药物靶点：AURK x Bcr-Abl T315I x IGF-1R x SRC_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

AURK x Bcr-Abl T315I x IGF-1R x SRC

作用机制

Bcr-Abl T315I抑制剂(bcr-abl酪氨酸激酶T315I抑制剂)、IGF-1R拮抗剂(胰岛素样生长因子-I受体拮抗剂)、SRC抑制剂(酪氨酸蛋白激酶SRC抑制剂)

+ [1]

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病

在研适应症-

非在研适应症

费城染色体阳性慢性粒细胞白血病淋巴瘤费城染色体阳性急性淋巴细胞白血病

原研机构

Exelixis, Inc.

在研机构-

非在研机构

Exelixis, Inc.

最高研发阶段终止临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C22H31N9O

InChIKeyALKJNCZNEOTEMP-UHFFFAOYSA-N

CAS号898280-07-4

关联

2

项与 XL-228 相关的临床试验

NCT00526838 / Terminated临床1期

A Phase 1 Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of XL228 Administered Intravenously to Subjects With Advanced Malignancies

The purpose of this study is to assess the safety and tolerability of the multi-targeted protein kinase inhibitor XL228 (active against IGF1R, Src, FGFR, and BCR-Abl) administered as a once- or twice-weekly 1-hour intravenous infusion in subjects with advanced malignancies.

开始日期2007-09-01

申办/合作机构

Exelixis, Inc.

NCT00464113 / Terminated临床1期

A Phase 1 Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of XL228 Administered Intravenously to Subjects With Chronic Myeloid Leukemia (CML) or Philadelphia-Chromosome-Positive Acute Lymphocytic Leukemia (Ph+ ALL)

The purpose of this study is to determine the safest dose of the BCR-ABL inhibitor XL228, how often it should be taken, and how well people with leukemia tolerate XL228.

开始日期2007-05-01

申办/合作机构

Exelixis, Inc.

100 项与 XL-228 相关的临床结果

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100 项与 XL-228 相关的转化医学

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100 项与 XL-228 相关的专利（医药）

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5

项与 XL-228 相关的文献（医药）

2021-01-01·OncoImmunology2区 · 医学

The PKN1- TRAF1 signaling axis as a potential new target for chronic lymphocytic leukemia

2区 · 医学

ArticleOA

作者: Mbanwi, Achire N. ; Prakesch, Michael ; Al-awar, Rima ; Zangiabadi, Safoura ; Ting, Kenneth ; Uehling, David ; Isaac, Methvin ; Arruda, Andrea ; Abdul-Sater, Ali A. ; Edilova, Maria I. ; Watts, Tania H. ; Minden, Mark D. ; Law, Jaclyn C.

TRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer. Here we show that the protein kinase C related kinase Protein Kinase N1 (PKN1) is required to protect TRAF1 from cIAP-mediated degradation during constitutive CD40 signaling in lymphoma. We show that the active phospho-Thr774 form of PKN1 is constitutively expressed in CLL but minimally detected in unstimulated healthy donor B cells. Through a screen of 700 kinase inhibitors, we identified two inhibitors, OTSSP167, and XL-228, that inhibited PKN1 in the nanomolar range and induced dose-dependent loss of TRAF1 in RAJI cells. OTSSP167 or XL-228 treatment of primary patient CLL samples led to a reduction in TRAF1, pNF-κB p65, pS6, pERK, Mcl-1 and Bcl-2 proteins, and induction of activated caspase-3. OTSSP167 synergized with venetoclax in inducing CLL death, correlating with loss of TRAF1, Mcl-1, and Bcl-2. Although correlative, these findings suggest the PKN1-TRAF1 signaling axis as a potential new target for CLL. These findings also suggest the use of the orally available inhibitor OTSSP167 in combination treatment with venetoclax for TRAF1 overexpressing CLL.

2012-06-01·Cancer Treatment Reviews1区 · 医学

The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors

1区 · 医学

Review

作者: Giorgio V. Scagliotti ; Silvia Novello

The type 1 insulin-like growth factor receptor (IGF-1R) and its downstream signaling components have become increasingly recognized as having a driving role in the development of malignancy, and consequently IGF-1R has become a potential target for cancer therapy. Several inhibitors of IGF-1R are in clinical development for the treatment of solid tumors, including non-small cell lung cancer (NSCLC). These IGF-1R-targeted agents include monoclonal antibodies such as cixutumumab (IMC-A12), AMG-479, AVE1642, BIIB022, dalotuzumab (MK-0646), and robatumumab (Sch717454), the ligand neutralizing antibody Medi-573, and the small molecule inhibitors BMS-754807, linsitinib (OSI-906), XL228, and AXL1717. Two phase III trials of the anti-IGF-1R monoclonal antibody, figitumumab (CP-751,871), were discontinued in 2010 as it was considered unlikely either trial would meet their primary endpoints. In light of disappointing clinical data with figitumumab and other targeted agents, it is likely that the use of molecular markers will become important in predicting response to treatment. This review outlines the role of IGF-1R signaling in solid tumors with a particular focus on NSCLC, and provides an overview of clinical data.

2012-01-01·Recent Patents on Anti-Cancer Drug Discovery4区 · 医学

Insulin-like Growth Factor: Current Concepts and New Developments in Cancer Therapy

4区 · 医学

Review

作者: Erin R. King ; Kwong Kwok Wong

The insulin-like growth factor (IGF) family and the IGF-1 receptor (IGF-1R) play an important role in cancer. This intricate and complex signaling pathway provides many opportunities for therapeutic intervention, and several novel therapeutics aimed at the IGF-1R, particularly monoclonal antibodies and small molecule tyrosine kinase inhibitors, are under clinical investigation. This article provides a patent overview of the IGF signaling pathway and its complexity, addresses the justification for the use of IGF-1R-targeted therapy, and reviews the results of in vivo and in vitro novel therapeutics. Over the past year, the completion of several phase I, II, and III trials have provided interesting new information about the clinical activity of these novel compounds, particularly CP-751,871, IMC-A12, R1507, AMG-479, AVE-1642, MK-0646, XL-228, OSI-906, and BMS-754807. We review the important preliminary results from clinical trials with these compounds and conclude with a discussion about future therapeutic efforts.

100 项与 XL-228 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
淋巴瘤	临床1期	美国	Exelixis, Inc.	2007-09-01
费城染色体阳性慢性粒细胞白血病	临床1期	美国	Exelixis, Inc.	2007-05-01
费城染色体阳性急性淋巴细胞白血病	临床1期	美国	Exelixis, Inc.	2007-05-01

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临床结果

适应症

分期

评价

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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


ASCO2009	临床1期	实体瘤 \| 血液肿瘤	-	XL228	鏇獵廠淵窪積構艱齋窪(夢遞遞選醖壓艱繭選夢) = requiring dose skipping 齋製鹹餘鹹鏇築餘積顧 (艱壓衊築齋壓醖淵鬱製 ) 更多	积极	2009-05-20