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Last update 08 May 2025

MASTL

Last update 08 May 2025

Basic Info

Synonyms

FLJ14813, greatwall kinase homolog, GW

+ [9]

Introduction

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.

Drugs associated with MASTL

AD-1208

Target

MASTL

Mechanism

MASTL inhibitors

Active Org.

Avelos Therapeutics

Originator Org.

Avelos Therapeutics

Active Indication

Advanced Malignant Solid Neoplasm [+2]

Inactive Indication-

Drug Highest PhasePhase 1/2

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

MASTL inhibitor(Pfizer)

Target

MASTL

Mechanism

MASTL inhibitors

Active Org.

Huizhi Pharmaceutical (Dalian) Co., Ltd.

Originator Org.

Huizhi Pharmaceutical (Dalian) Co., Ltd.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

MASTL inhibitors(Pfizer Worldwide Services Unlimited)

Target

MASTL

Mechanism

MASTL inhibitors

Active Org.

Pfizer Worldwide Services Unlimited Co.

Originator Org.

Pfizer Worldwide Services Unlimited Co.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with MASTL

NCT06911333

/ RecruitingPhase 1/2

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

Start Date11 Mar 2025

Sponsor / Collaborator

Avelos Therapeutics

100 Clinical Results associated with MASTL

100 Translational Medicine associated with MASTL

0 Patents (Medical) associated with MASTL

190

Literatures (Medical) associated with MASTL

31 Dec 2024·Journal of Enzyme Inhibition and Medicinal Chemistry

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

Article

Author: 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.

01 Dec 2024·Development

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

Article

Author: 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.

14 Nov 2024·Journal of Medicinal Chemistry

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

Article

Author: 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.

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