TAK-901(TAK-901) - 药物靶点：Aurora B_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

Aurora B

作用机制

Aurora B抑制剂(丝氨酸/苏氨酸蛋白激酶Aurora-B抑制剂)

治疗领域

肿瘤免疫系统疾病心血管疾病+ [2]

在研适应症-

非在研适应症

急性淋巴细胞白血病急性髓性白血病晚期恶性实体瘤+ [10]

原研机构

Takeda Pharmaceutical Co., Ltd.

在研机构-

非在研机构

Millennium Pharmaceuticals, Inc.

Millennium Biotechnologies, 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-

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结构

分子式C28H32N4O3S

InChIKeyWKDACQVEJIVHMZ-UHFFFAOYSA-N

CAS号934541-31-8

关联

2

项与 TAK-901 相关的临床试验

NCT00935844 / Completed临床1期

An Open-Label, Dose Escalation, Phase I Study of TAK-901 in Adult Patients With Advanced Solid Tumors or Lymphoma

This study is being conducted to evaluate the safety profile and the Maximum Tolerated Dose (MTD) of TAK-901 in adult patients with advanced solid tumors or lymphoma. This study will help to identify the recommended phase 2 dose and infusion duration, and describe the pharmacokinetics of TAK-901.

开始日期2009-10-01

申办/合作机构

Millennium Pharmaceuticals, Inc.

NCT00807677 / Completed临床1期

A Phase 1 Dose Escalation Study of TAK-901 in Subjects With Advanced Hematologic Malignancies

The purpose of this study is to determine the maximum tolerated dose (MTD) of TAK-901 in subjects with advanced hematological malignancies, and to further assess the safety and tolerability of TAK-901 at or below the MTD in an expanded cohort of subjects in order to select a dose for future studies.

开始日期2009-03-01

申办/合作机构

Millennium Pharmaceuticals, Inc.

100 项与 TAK-901 相关的临床结果

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100 项与 TAK-901 相关的转化医学

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100 项与 TAK-901 相关的专利（医药）

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7

项与 TAK-901 相关的文献（医药）

2020-12-01·Clinical Epigenetics2区 · 医学

Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

2区 · 医学

ArticleOA

作者: Varma, Sudhir ; Connelly, John ; Rapisarda, Annamaria ; Pommier, Yves ; Meltzer, Paul S ; Reinhold, William C ; Kunkel, Mark ; Sonkin, Dmitriy ; Vural, Suleyman ; Krushkal, Julia ; Silvers, Thomas ; Evans, David ; Teicher, Beverly A

AbstractBackgroundSmall cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. SCLC progression and treatment resistance involve epigenetic processes. However, links between SCLC DNA methylation and drug response remain unclear. We performed an epigenome-wide study of 66 human SCLC cell lines using the Illumina Infinium MethylationEPIC BeadChip array. Correlations of SCLC DNA methylation and gene expression with in vitro response to 526 antitumor agents were examined.ResultsWe found multiple significant correlations between DNA methylation and chemosensitivity. A potentially important association was observed for TREX1, which encodes the 3′ exonuclease I that serves as a STING antagonist in the regulation of a cytosolic DNA-sensing pathway. Increased methylation and low expression of TREX1 were associated with the sensitivity to Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901; the CDK inhibitor R-547; the Vertex ATR inhibitor Cpd 45; and the mitotic spindle disruptor vinorelbine. Compared with cell lines of other cancer types, TREX1 had low mRNA expression and increased upstream region methylation in SCLC, suggesting a possible relationship with SCLC sensitivity to Aurora kinase inhibitors.We also identified multiple additional correlations indicative of potential mechanisms of chemosensitivity. Methylation of the 3′UTR of CEP350 and MLPH, involved in centrosome machinery and microtubule tracking, respectively, was associated with response to Aurora kinase inhibitors and other agents. EPAS1 methylation was associated with response to Aurora kinase inhibitors, a PLK-1 inhibitor and a Bcl-2 inhibitor. KDM1A methylation was associated with PLK-1 inhibitors and a KSP inhibitor. Increased promoter methylation of SLFN11 was correlated with resistance to DNA damaging agents, as a result of low or no SLFN11 expression. The 5′ UTR of the epigenetic modifier EZH2 was associated with response to Aurora kinase inhibitors and a FGFR inhibitor. Methylation and expression of YAP1 were correlated with response to an mTOR inhibitor. Among non-neuroendocrine markers, EPHA2 was associated with response to Aurora kinase inhibitors and a PLK-1 inhibitor and CD151 with Bcl-2 inhibitors.ConclusionsMultiple associations indicate potential epigenetic mechanisms affecting SCLC response to chemotherapy and suggest targets for combination therapies. While many correlations were not specific to SCLC lineages, several lineage markers were associated with specific agents.

2017-02-10·Anticancer Research4区 · 医学

Aurora B Inhibitor TAK-901 Synergizes with BCL-xL Inhibition by Inducing Active BAX in Cancer Cells

4区 · 医学

Article

作者: Miya, Hiroyuki ; Murai, Saomi ; Matuszkiewicz, Jennifer ; DE Jong, Ron ; Okuzono, Yuumi

BACKGROUNDAurora B kinase plays an essential role in chromosome segregation and cytokinesis, and is dysregulated in many cancer types, making it an attractive therapeutic target. TAK-901 is a potent aurora B inhibitor that showed efficacy in both in vitro and in vivo oncology models.MATERIALS AND METHODSWe conducted a synthetic lethal siRNA screening to identify the genes that, when silenced, can potentiate the cell growth-inhibitory effect of TAK-901.RESULTSB-cell lymphoma-extra large (BCL-xL) depletion by siRNA or chemical inhibition synergized with TAK-901 in cancer cell lines. As a mechanism of synthetic lethality, active BCL2 associated X, apoptosis regulator (BAX) was induced by TAK-901. BCL-xL protected cells from BAX-dependent apoptosis induction. Therefore, TAK-901 sensitizes cancer cells to BCL-xL inhibition.CONCLUSIONPolyploid cells induced by TAK-901 are vulnerable to BCL-xL inhibition. Our findings may have an impact on combination strategies with aurora B inhibitors in clinical studies.

2015-07-10·Current Cancer Drug Targets4区 · 医学

Structural Biology Insight for the Design of Sub-type Selective Aurora Kinase Inhibitors

4区 · 医学

Review

作者: Sarvagalla, Sailu ; Coumar, Mohane Selvaraj

Aurora kinase A, B and C, are key regulators of mitosis and are over expressed in many of the human cancers, making them an ideal drug target for cancer chemotherapy. Currently, over a dozen of Aurora kinase inhibitors are in various phases of clinical development. The majority of the inhibitors (VX-680/MK-0457, PHA-739358, CYC116, SNS-314, AMG 900, AT-9283, SCH- 1473759, ABT-348, PF-03814735, R-763/AS-703569, KW-2449 and TAK-901) are pan-selective (isoform non-selective) and few are Aurora A (MLN8054, MLN8237, VX-689/MK5108 and ENMD 2076) and Aurora B (AZD1152 and GSK1070916) sub-type selective. Despite the intensive research efforts in the past decade, no Aurora kinase inhibitor has reached the market. Recent evidence suggests that the sub-type selective Aurora kinase A inhibitor could possess advantages over pan-selective Aurora inhibitors, by avoiding Aurora B mediated neutropenia. However, sub-type selective Aurora kinase A inhibitor design is very challenging due to the similarity in the active site among the isoforms. Structural biology and computational aspects pertaining to the design of Aurora kinase inhibitors were analyzed and found that a possible means to develop sub-type selective inhibitor is by targeting Aurora A specific residues (Leu215, Thr217 and Arg220) or Aurora B specific residues (Arg159, Glu161 and Lys164), near the solvent exposed region of the protein. Particularly, a useful strategy for the design of sub-type selective Aurora A inhibitor could be by targeting Thr217 residue as in the case of MLN8054. Further preclinical and clinical studies with the sub-type selective Aurora inhibitors could help bring them to the market for the treatment of cancer.

100 项与 TAK-901 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12756

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
急性髓性白血病	临床2期	美国	Millennium Pharmaceuticals, Inc.	2009-03-01
急性淋巴细胞白血病	临床1期	美国	Millennium Pharmaceuticals, Inc.	2009-03-01
慢性淋巴细胞白血病	临床1期	美国	Millennium Pharmaceuticals, Inc.	2009-03-01
多发性骨髓瘤	临床1期	美国	Millennium Pharmaceuticals, Inc.	2009-03-01
骨髓增生异常综合征	临床1期	美国	Millennium Pharmaceuticals, Inc.	2009-03-01
费城染色体阳性慢性粒细胞白血病	临床1期	美国	Millennium Pharmaceuticals, Inc.	2009-03-01
巨球蛋白血症	临床1期	美国	Millennium Pharmaceuticals, Inc.	2009-03-01
淋巴瘤	临床1期	美国	Millennium Biotechnologies, Inc.	-
实体瘤	临床1期	美国	Millennium Biotechnologies, Inc.	-
红细胞增多症	药物发现	美国	Millennium Pharmaceuticals, Inc.	2009-03-01