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更新于：2025-05-07

MASTL

更新于：2025-05-07

基本信息

别名

FLJ14813、greatwall kinase homolog、GW

+ [9]

简介

Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance (PubMed:19680222). Acts by promoting the inactivation of protein phosphatase 2A (PP2A) during M phase: does not directly inhibit PP2A but acts by mediating phosphorylation and subsequent activation of ARPP19 and ENSA at 'Ser-62' and 'Ser-67', respectively (PubMed:38123684). ARPP19 and ENSA are phosphatase inhibitors that specifically inhibit the PPP2R2D (PR55-delta) subunit of PP2A. Inactivation of PP2A during M phase is essential to keep cyclin-B1-CDK1 activity high (PubMed:20818157). Following DNA damage, it is also involved in checkpoint recovery by being inhibited. Phosphorylates histone protein in vitro; however such activity is unsure in vivo. May be involved in megakaryocyte differentiation.

关联

项与 MASTL 相关的药物

AD-1208

靶点

MASTL

作用机制

MASTL 抑制剂

在研机构

Avelos Therapeutics

原研机构

Avelos Therapeutics

在研适应症

晚期恶性实体瘤 [+2]

非在研适应症-

最高研发阶段临床1/2期

首次获批国家/地区-

首次获批日期1800-01-20

MASTL inhibitor(Pfizer)

MASTL抑制剂(辉瑞制药)

靶点

MASTL

作用机制

MASTL 抑制剂

在研机构

辉瑞制药有限公司

原研机构

辉瑞制药有限公司

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

MASTL inhibitors(Pfizer Worldwide Services Unlimited)

靶点

MASTL

作用机制

MASTL 抑制剂

在研机构

Pfizer Worldwide Services Unlimited Co.

原研机构

Pfizer Worldwide Services Unlimited Co.

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

项与 MASTL 相关的临床试验

NCT06911333

/ Recruiting临床1/2期

A Phase I/IIa Trial of AD1208, a Cell Cycle Inhibitor/MASTL Inhibitor, as a Single Agent or a Combination in Subjects With Any Progressive, Locally Advanced(Unresectable) or Metastatic Solid Tumors

The goal of this clinical trial is to evaluate the safety and tolerability of AD1208 to determine the maximum tolerated dose(MTD) or maximumly administered dose(MAD) in any progressive, locally advanced (unresectable) or metastatic solid tumors. The main questions it aims to answer are:
* Which dosage of AD1208 is safe and tolerable for participants?
* What medical problems do participants have when taking AD1208?
Participants will:
* Take drug AD1208 every day up to 1 cycle at the least.
* Visit the site once every 1 weeks for checkups and tests during cycle 1 and every 3 weeks from cycle 2 onwards.
* Keep a diary of any adverse events and administrated drug

开始日期2025-03-11

申办/合作机构

Avelos Therapeutics

100 项与 MASTL 相关的临床结果

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100 项与 MASTL 相关的转化医学

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0 项与 MASTL 相关的专利（医药）

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190

项与 MASTL 相关的文献（医药）

2024-12-31·Journal of Enzyme Inhibition and Medicinal Chemistry

Design and synthesis of doublecortin-like kinase 1 inhibitors and their bioactivity evaluation

Article

作者: Pan, Pengming ; Ji, Dengbo ; Meng, Xiangbao ; Li, Zhongjun

Doublecortin-like kinase 1 (DCLK) is a microtubule-associated serine/threonine kinase that is upregulated in a wide range of cancers and is believed to be related to tumour growth and development. Upregulated DCLK1 has been used to identify patients at high risk of cancer progression and tumours with chemotherapy-resistance. Moreover, DCLK1 has been identified as a cancer stem cell (CSC) biomarker in various cancers, which has received considerable attention recently. Herein, a series of DCLK1 inhibitors were prepared based on the previously reported XMD8-92 structure. Among all the synthesised compounds, D1, D2, D6, D7, D8, D12, D14, and D15 showed higher DCLK1 inhibitory activities (IC₅₀ 40-74 nM) than XMD8-92 (IC₅₀ 161 nM). Compounds D1 and D2 were selective DCLK1 inhibitors as they showed a rather weak inhibitory effect on LRRK2. The antiproliferative activities of these compounds were also preliminarily evaluated. The structure-activity relationship revealed by our compounds provides useful guidance for the further development of DCLK1 inhibitors.

2024-12-01·Development

ARPP19 phosphorylation site evolution and the switch in cAMP control of oocyte maturation in vertebrates

Article

作者: Lapébie, Pascal ; Le, Tran ; Daldello, Enrico Maria ; Chevalier, Sandra ; Miot, Marika ; Jessus, Catherine ; Houliston, Evelyn ; Assaf, Sarah ; Meneau, Ferdinand

ABSTRACTcAMP-PKA signaling initiates the crucial process of oocyte meiotic maturation in many animals, but inhibits it in vertebrates. To address this ‘cAMP paradox’, we exchanged the key PKA substrate ARPP19 between representative species, the vertebrate Xenopus and the cnidarian Clytia, comparing its phosphorylation and function. We found that, as in Xenopus, Clytia maturing oocytes undergo ARPP19 phosphorylation on a highly conserved Gwl site, which inhibits PP2A and promotes M-phase entry. In contrast, despite a PKA phosphorylation signature motif recognizable across most animals, Clytia ARPP19 was only poorly phosphorylated by PKA in vitro and in vivo. Furthermore, unlike Xenopus ARPP19, exogenous Clytia ARPP19 did not delay Xenopus oocyte maturation. We conclude that, in Clytia, ARPP19 does not intervene in oocyte maturation initiation because of both poor recognition by PKA and the absence of effectors that mediate vertebrate oocyte prophase arrest. We propose that ancestral ARPP19 phosphorylated by Gwl has retained a key role in M-phase across eukaryotes and has acquired new functions during animal evolution mediated by enhanced PKA phosphorylation, allowing co-option into oocyte maturation regulation in the vertebrate lineage.

2024-11-14·Journal of Medicinal Chemistry

Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL)

Article

作者: Elleraas, Jeff ; Tran-Dubé, Michelle ; Salomon-Ferrer, Romelia ; Brun, Sonja ; Gallego, Rebecca A. ; Wang, Fen ; Zou, Aihua ; Bernier, Louise ; Ewanicki, Jason ; Quinlan, Casey L. ; Dress, Klaus ; Johnson, Ted W. ; Wythes, Martin ; Lafontaine, Jennifer ; Toledo, Chad ; VanArsdale, Todd ; Patman, Ryan L. ; Linton, Angelica ; Li, Jian ; Berry, Madeline ; Eisele, Koleen ; Greasley, Samantha ; Fobian, Yvette ; Murtaza, Anwar ; Tran, Phuong ; Wang, Wei ; Khamphavong, Penney ; Miller, Nichol ; Sach, Neal ; Silva, Francisco ; Yang, Shouliang ; Maestre, Michael ; Diehl, Wade ; Greenwald, Eric C. ; McAlpine, Indrawan ; Timofeevski, Sergei ; Chung, Loanne ; Auth, Marin ; Scales, Stephanie ; Richardson, Paul ; Davis, Carl ; Ramms, Dana J.

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis. The resulting advanced lead compounds enabled a tumor growth inhibition study which was pivotal in assessing the potential value of MASTL as an oncology therapeutic target.

项与 MASTL 相关的新闻（医药）

2024-05-08

·医药观澜

开发小分子抗癌药，新锐获超9000万元B轮融资

近日，韩国生物医药公司Avelos Therapeutics宣布获得170亿韩元（约合9010万元人民币）B轮投资。至此，该公司总融资达到300亿韩元，其中包括近20亿韩元的种子轮融资以及100亿韩元的A轮融资。Avelos公司成立于2021年9月，致力于在合成致死、DNA损伤反应以及细胞周期调节等领域开发小分子抗癌新药。根据Avelos公司公开资料，该公司研发管线中包括了4款在研抗癌新药。其中进展最快的AVS1001是一款潜在“first-inclass”口服MASTL激酶抑制剂，旨在影响细胞周期和DNA损伤反应。微管相关丝氨酸/苏氨酸激酶样（MASTL）是一种重要的有丝分裂激酶，它通过阻断肿瘤抑制蛋白磷酸酶2A（PP2A）的活性来调节正常或转化细胞的有丝分裂进程。目前，靶向有丝分裂激酶已经成为一种新兴的抗癌方法。 AVS1001有望治疗对现有药物无反应的癌症患者，包括结肠癌、胃癌、乳腺癌、卵巢癌、前列腺癌等多种癌症。在实验室和动物实验中，AVS1001在选择性抑制癌细胞而不是正常细胞方面都表现出了较为出色的功效。AVS1001的临床前研究数据已经在今年美国癌症研究协会（AACR 2024）披露。Avelos公司计划于今年下半年开始该产品的临床研究。 Avelos公司还在开发其它3款针对DNA损伤反应的候选药物，其中AVS1002被确定为治疗DNA损伤反应中同源重组缺陷（HRD）患者的候选药物。参考资料： [1]아벨로스테라퓨틱스, 시리즈B 170억 투자유치…총 300억 규모 조달. Retrieved May 2, 2024, from http://www.avelostx.com/en/sub/media/news.asp?mode=view&bid=1&s_type=&s_keyword=&s_cate=&idx=42&page=1 [2]Avelos公司官网. From http://www.avelostx.com 内容来源于网络，如有侵权，请联系删除。

AACR会议临床结果