TAS-4464(TAS-4464) - 药物靶点：NAE_在研适应症：多发性骨髓瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

NAE

作用机制

NAE抑制剂(NEDD8激活酶复合体抑制剂)

治疗领域

肿瘤免疫系统疾病心血管疾病+ [1]

在研适应症

多发性骨髓瘤

非在研适应症

子宫内膜癌实体瘤

原研机构

Taiho Pharmaceutical Co., Ltd.

在研机构

Taiho Pharmaceutical Co., Ltd.

非在研机构

Taiho Oncology, Inc.

最高研发阶段临床2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C21H24ClFN6O6S

InChIKeyCDCFJYCKNAWPTL-WVAMHNCPSA-N

CAS号1848959-11-4

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关联

3

项与 TAS-4464 相关的临床试验

NCT02978235 / Terminated临床1期

A Phase 1, Open-Label Safety, Pharmacokinetic and Efficacy Study of TAS4464 in Patients With Multiple Myeloma or Lymphoma

The Phase 1 portion of this study will determine the safety of TAS4464 and the most appropriate dose for patients with Multiple Myeloma or Lymphoma.

开始日期2017-03-01

申办/合作机构

Taiho Oncology, Inc.

JPRN-jRCT2080223433 / Completed临床1期

A PHASE IA/IB, OPEN-LABEL, SAFETY, TOLERABILITY, PHARMACOKINETIC, AND EFFICACY STUDY OF TAS4464 IN PATIENTS WITH ADVANCED MALIGNANCIES

开始日期2017-02-27

申办/合作机构

Taiho Pharmaceutical Co., Ltd.

JPRN-JapicCTI-173488 / Completed临床1期

A PHASE IA/IB, OPEN-LABEL, SAFETY, TOLERABILITY, PHARMACOKINETIC, AND EFFICACY STUDY OF TAS4464 IN PATIENTS WITH ADVANCED MALIGNANCIES

开始日期2017-02-27

申办/合作机构

Taiho Pharmaceutical Co., Ltd.

100 项与 TAS-4464 相关的临床结果

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100 项与 TAS-4464 相关的转化医学

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100 项与 TAS-4464 相关的专利（医药）

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7

项与 TAS-4464 相关的文献（医药）

2021-08-01·Investigational New Drugs3区 · 医学

A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

3区 · 医学

Article

作者: Tomomatsu, Junichi ; Iwasa, Satoru ; Kitano, Shigehisa ; Sato, Jun ; Sudo, Kazuki ; Koyama, Takafumi ; Takahashi, Shunji ; Yonemori, Kan ; Yamamoto, Noboru ; Tamura, Kenji ; Fukuda, Naoki ; Ono, Makiko ; Kondo, Shunsuke ; Shimizu, Toshio

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

2021-02-18·Oncogene1区 · 医学

TAS4464, a NEDD8-activating enzyme inhibitor, activates both intrinsic and extrinsic apoptotic pathways via c-Myc-mediated regulation in acute myeloid leukemia

1区 · 医学

Article

作者: Yokoyama, Masataka ; Ochiiwa, Hiroaki ; Nakayama, Akitoshi ; Nagano, Hidekazu ; Haruma, Tomonori ; Tanaka, Tomoaki ; Yoshimura, Chihoko ; Murata, Kazutaka ; Nishimura, Motoi ; Ohara, Osamu ; Kawashima, Yusuke ; Ailiken, Guzhanuer ; Ohkubo, Shuichi ; Ishida, Keiji ; Yamagata, Kazuyuki ; Hashimoto, Naoko ; Muraoka, Hiromi

AbstractTAS4464, a potent, selective small molecule NEDD8-activating enzyme (NAE) inhibitor, leads to inactivation of cullin-RING E3 ubiquitin ligases (CRLs) and consequent accumulations of its substrate proteins. Here, we investigated the antitumor properties and action mechanism of TAS4464 in acute myeloid leukemia (AML). TAS4464 induced apoptotic cell death in various AML cell lines. TAS4464 treatments resulted in the activation of both the caspase-9-mediated intrinsic apoptotic pathway and caspase-8-mediated extrinsic apoptotic pathway in AML cells; combined treatment with inhibitors of these caspases markedly diminished TAS4464-induced apoptosis. In each apoptotic pathway, TAS4464 induced the mRNA transcription of the intrinsic proapoptotic factor NOXA and decreased that of the extrinsic antiapoptotic factor c-FLIP. RNA-sequencing analysis showed that the signaling pathway of the CRL substrate c-Myc was enriched after TAS4464 treatment. Chromatin immunoprecipitation (ChIP) assay revealed that TAS4464-induced c-Myc bound to the PMAIP1 (encoding NOXA) and CFLAR (encoding c-FLIP) promoter regions, and siRNA-mediated c-Myc knockdown neutralized both TAS4464-mediated NOXA induction and c-FLIP downregulation. TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism.

2019-12-01·Cancer Science

Activity of TAS4464, a novel NEDD8 activating enzyme E1 inhibitor, against multiple myeloma via inactivation of nuclear factor κB pathways

Article

作者: Matsuo, Kenichi ; Kawabata, Rumi ; Nakagawa, Fumio ; Ochiiwa, Hiroaki ; Ohkubo, Shuichi ; Tsuji, Shingo ; Yoshimura, Chihoko ; Muraoka, Hiromi ; Fujioka, Yayoi ; Hashimoto, Akihiro

AbstractThe ubiquitin proteasome pathway is essential for the proliferation and survival of multiple myeloma (MM) cells. TAS4464, a novel highly potent inhibitor of NEDD8 activating enzyme, selectively inactivates cullin‐RING ubiquitin E3 ligases, resulting in accumulation of their substrates. Here, we examined 14 MM cell lines treated with TAS4464. TAS4464 induced growth arrest and cell death in the MM cell lines even in the presence of bone marrow stromal cells. It also induced the accumulation of phospho‐inhibitor of κBα and phospho‐p100, impaired the activities of nuclear factor κB (NF‐κB) transcription factors p65 and RelB, and decreased the expression of NF‐κB target genes, suggesting that TAS4464 inhibits both the canonical and non–canonical NF‐κB pathways. TAS4464 had similar effects in an in vivo human‐MM xenograft mouse model in which it was also observed to have strong antitumor effects. TAS4464 synergistically enhanced the antitumor activities of the standard MM chemotherapies bortezomib, lenalidomide/dexamethasone, daratumumab and elotuzumab. Together, these results suggest that the anti–MM activity of TAS4464 occurs via inhibition of the NF‐κB pathways, and that treatment with TAS4464 is a potential approach for treating MM by single and combination therapies.

100 项与 TAS-4464 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
多发性骨髓瘤	临床2期	-	Taiho Pharmaceutical Co., Ltd.	-
子宫内膜癌	临床前	日本	Taiho Pharmaceutical Co., Ltd.	-
实体瘤	临床前	美国	Taiho Pharmaceutical Co., Ltd.	-
实体瘤	临床前	欧盟	Taiho Pharmaceutical Co., Ltd.	-