Delving into the Latest Updates on TAK-901 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Aurora B

Mechanism

Aurora B inhibitors(Serine/threonine-protein kinase Aurora-B inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesCardiovascular Diseases+ [2]

Active Indication-

Inactive Indication

Acute Lymphoblastic LeukemiaAcute Myeloid LeukemiaAdvanced Malignant Solid Neoplasm+ [10]

Originator Organization

Takeda Pharmaceutical Co., Ltd.

Active Organization-

Inactive Organization

Millennium Pharmaceuticals, Inc.

Millennium Biotechnologies, Inc.

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC28H32N4O3S

InChIKeyWKDACQVEJIVHMZ-UHFFFAOYSA-N

CAS Registry934541-31-8

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.

Start Date01 Mar 2009

Sponsor / Collaborator

Millennium Pharmaceuticals, Inc.

100 Clinical Results associated with TAK-901

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100 Translational Medicine associated with TAK-901

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100 Patents (Medical) associated with TAK-901

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7

Literatures (Medical) associated with TAK-901

01 Dec 2020·Clinical EpigeneticsQ2 · MEDICINE

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

Q2 · MEDICINE

ArticleOA

Author: Varma, Sudhir ; Rapisarda, Annamaria ; Connelly, John ; Meltzer, Paul S ; Reinhold, William C ; Pommier, Yves ; 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.

10 Feb 2017·Anticancer ResearchQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: 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.

10 Jul 2015·Current Cancer Drug TargetsQ4 · MEDICINE

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

Q4 · MEDICINE

Review

Author: 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 Deals associated with TAK-901

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12756

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Myelofibrosis	Phase 2	US	Millennium Pharmaceuticals, Inc.	01 Mar 2009
Polycythemia	Phase 2	US	Millennium Pharmaceuticals, Inc.	01 Mar 2009
Primary Myelofibrosis	Phase 2	US	Millennium Pharmaceuticals, Inc.	01 Mar 2009
Chronic Lymphocytic Leukemia	Phase 1	US	Millennium Pharmaceuticals, Inc.	01 Mar 2009
Multiple Myeloma	Phase 1	US	Millennium Pharmaceuticals, Inc.	01 Mar 2009
Philadelphia chromosome positive chronic myelogenous leukemia	Phase 1	US	Millennium Pharmaceuticals, Inc.	01 Mar 2009
Waldenstrom Macroglobulinemia	Phase 1	US	Millennium Pharmaceuticals, Inc.	01 Mar 2009
Lymphoma	Phase 1	US	Millennium Biotechnologies, Inc.	-
Solid tumor	Phase 1	US	Millennium Biotechnologies, Inc.	-
Acute Myeloid Leukemia	Preclinical	US	Millennium Pharmaceuticals, Inc.	01 Mar 2009