Last update 01 Nov 2024

GAK

Last update 01 Nov 2024

Basic Info

Synonyms

auxilin-2, cyclin G associated kinase, Cyclin-G-associated kinase

+ [2]

Introduction

Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1.

Drugs associated with GAK

SGC-GAK-1

Target

GAK

Mechanism

GAK inhibitors

Active Org.

The University of North Carolina at Chapel Hill

Originator Org.

The University of North Carolina at Chapel Hill

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GAK inhibitors(KU Leuven)

Target

GAK

Mechanism

GAK inhibitors

Active Org.

Katholieke Universiteit Leuven

Originator Org.-

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

EphA2/GAK inhibitors(Structural Genomics Consortium)

Target

EphA2 x GAK

Mechanism

EphA2 antagonists [+1]

Active Org.

Structural Genomics Consortium

Originator Org.

Structural Genomics Consortium

Active Indication

Dengue

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GAK

100 Translational Medicine associated with GAK

0 Patents (Medical) associated with GAK

297

Literatures (Medical) associated with GAK

31 Dec 2024·Emerging Microbes & Infections

Numb-associated kinases regulate sandfly-borne Toscana virus entry

Article

Author: Luxenburg, Chen ; Borenstein-Auerbach, Nofit ; Yaffe, Yakey ; Maoz, Ben M ; Perlson, Eran ; Raved, Roey ; Subramaniam, Anand G ; Malis, Yehonathan ; Einav, Shirit ; Tadmor, Keshet ; Sklan, Ella H ; Katz, Rodolfo ; Moalem, Yarden ; Lustig, Yaniv ; Yoo, Ji Seung

Sandfly-borne Toscana virus (TOSV) is an enveloped tri-segmented negative single-strand RNA Phlebovirus. It is an emerging virus predominantly endemic in southwestern Europe and Northern Africa. Although TOSV infection is typically asymptomatic or results in mild febrile disease, it is neurovirulent and ranks among the three most common causes of summer meningitis in certain regions. Despite this clinical significance, our understanding of the molecular aspects and host factors regulating phlebovirus infection is limited. This study characterized the early steps of TOSV infection. Our findings reveal that two members of the Numb-associated kinases family of Ser/Thr kinases, namely adaptor-associated kinase 1 (AAK1) and cyclin G-associated kinase (GAK), play a role in regulating the early stages of TOSV entry. FDA-approved inhibitors targeting these kinases demonstrated significant inhibition of TOSV infection. This study suggests that AAK1 and GAK represent druggable targets for inhibiting TOSV infection and, potentially, related Phleboviruses.

01 Dec 2024·Neural Regeneration Research

Dysfunction of synaptic endocytic trafficking in Parkinson’s disease

Article

Author: Ng, Xin Yi ; Cao, Mian

Parkinson’s disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum. The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive. Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson’s disease. Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway. This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson’s disease, followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a “dying back” mechanism. Recently, several new animal and cellular models with Parkinson’s disease-linked mutations affecting the endocytic pathway have been created and extensively characterized. These models faithfully recapitulate certain Parkinson’s disease-like features at the animal, circuit, and cellular levels, and exhibit defects in synaptic membrane trafficking, further supporting the findings from human genetics and clinical studies. In this review, we will first summarize the cellular and molecular findings from the models of two Parkinson’s disease-linked clathrin uncoating proteins: auxilin (DNAJC6/PARK19) and synaptojanin 1 (SYNJ1/PARK20). The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect. Subsequently, we will delve into the involvement of several clathrin-mediated endocytosis-related proteins (GAK, endophilin A1, SAC2/INPP5F, synaptotagmin-11), identified as Parkinson’s disease risk factors through genome-wide association studies, in Parkinson’s disease pathogenesis. We will also explore the direct or indirect roles of some common Parkinson’s disease-linked proteins (alpha-synuclein (PARK1/4), Parkin (PARK2), and LRRK2 (PARK8)) in synaptic endocytic trafficking. Additionally, we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways, particularly autophagy. Given that synaptic dysfunction is considered as an early event in Parkinson’s disease, a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel targets for early diagnosis and the development of interventional therapies for Parkinson’s disease. Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson’s disease.

08 Aug 2024·Journal of Medicinal Chemistry

Back-Pocket Optimization of 2-Aminopyrimidine-Based Macrocycles Leads to Potent EPHA2/GAK Kinase Inhibitors

Article

Author: Zhubi, Rezart ; Karim, Marwah ; Tran, Do Hoang Nhu ; Saxena, Krishna ; Berger, Benedict-Tilman ; Joerger, Andreas C ; Einav, Shirit ; Krämer, Andreas ; Ehret, Theresa A L ; Lenz, Christopher ; Elson, Lewis ; Berger, Lena M ; Knapp, Stefan ; Gerninghaus, Joshua ; Hanke, Thomas ; Müller, Susanne ; Schreiber, Christian

Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these compounds as chemical tools for the ephrin kinase family. Starting with a promiscuous macrocyclic inhibitor, 6, we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases. The crystal structure of EPHA2 in complex with the developed macrocycle 23 provided a basis for further optimization by specifically targeting the back pocket, resulting in compound 55, a potent inhibitor of EPHA2/A4 and GAK. Subsequent front-pocket derivatization resulted in an interesting in cellulo selectivity profile, favoring EPHA4 over the other ephrin receptor kinase family members. The dual EPHA2/A4 and GAK inhibitor 55 prevented dengue virus infection of Huh7 liver cells. However, further investigations are needed to determine whether this was a compound-specific effect or target-related.

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GAK

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