Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors

Voura, Maria; Anwar, Saleha; Sigala, Ioanna; Parasidou, Eleftheria; Fragoulidou, Souzanna; Hassan, Md. Imtaiyaz; Sarli, Vasiliki

doi:10.1021/acsptsci.3c00084

Cited by 5 publications

(3 citation statements)

References 55 publications

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“…Collectively, there is evidence pointing to a proatherogenic role for MARK4 ( Figure 4 ), rendering this kinase a potential therapeutic target in atherosclerosis. Therefore, MARK4 inhibitors, such as MARK4 inhibitors 1–4 [ 128 ], may be worth exploring in an atherosclerosis model.…”

Section: Camk-like Familymentioning

confidence: 99%

Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis

Teuwen,

van der Vorst,

Maas

2024

IJMS

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Circulating low-density lipoprotein (LDL) levels are a major risk factor for cardiovascular diseases (CVD), and even though current treatment strategies focusing on lowering lipid levels are effective, CVD remains the primary cause of death worldwide. Atherosclerosis is the major cause of CVD and is a chronic inflammatory condition in which various cell types and protein kinases play a crucial role. However, the underlying mechanisms of atherosclerosis are not entirely understood yet. Notably, protein kinases are highly druggable targets and represent, therefore, a novel way to target atherosclerosis. In this review, the potential role of the calcium/calmodulin-dependent protein kinase-like (CaMKL) family and its role in atherosclerosis will be discussed. This family consists of 12 subfamilies, among which are the well-described and conserved liver kinase B1 (LKB1) and 5′ adenosine monophosphate-activated protein kinase (AMPK) subfamilies. Interestingly, LKB1 plays a key role and is considered a master kinase within the CaMKL family. It has been shown that LKB1 signaling leads to atheroprotective effects, while, for example, members of the microtubule affinity-regulating kinase (MARK) subfamily have been described to aggravate atherosclerosis development. These observations highlight the importance of studying kinases and their signaling pathways in atherosclerosis, bringing us a step closer to unraveling the underlying mechanisms of atherosclerosis.

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Section: Camk-like Familymentioning

confidence: 99%

Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis

Teuwen,

van der Vorst,

Maas

2024

IJMS

View full text Add to dashboard Cite

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“…95 Several bioactive molecules might provide optimized lead applicants in drug discovery for tumor treatment by inhibiting MARK4. 71,109 MARK4 is a significant target, and its inhibitors might be utilized as potential drugs. 70,95 It might be a target for antitumor medication improvement.…”

Section: Mark4 Mutationsmentioning

confidence: 99%

Therapeutic targeting of microtubule affinity‐regulating kinase 4 in cancer and neurodegenerative diseases

Alam,

Ahmed,

Abid

et al. 2023

J of Cellular Biochemistry

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Microtubule affinity‐regulating kinase 4 (MARK4) is a member of the Ser/Thr protein kinase family, phosphorylates the microtubule‐connected proteins and plays a vital role in causing cancers and neurodegenerative diseases. This kinase modulates multiple signaling pathways, including mammalian target of rapamycin, nuclear factor‐κB, and Hippo‐signaling, presumably responsible for cancer and Alzheimer's. MARK4 acts as a negative controller of the Hippo‐kinase cassette for promoting YAP/TAZ action, and the loss of MARK4 detains the tumorigenic properties of cancer cells. MARK4 is involved in tau hyperphosphorylation that consequently affects neurodegeneration. MARK4 is a promising drug target for cancer, diabetes, and Alzheimer's. Developing the potent and selective inhibitors of MAKR4 are promising in the therapeutic management of associated diseases. Despite its great significance, a few reviews are available to discuss its structure, function and clinical significance. In the current review, we aimed to provide detailed information on the structural features of MARK4 targeted in drug development and its role in various signaling pathways related to cancer and neurodegenerative diseases. We further described the therapeutic potential of MARK4 inhibitors in preventing numerous diseases. Finally, the updated information on MARK4 will be helpful in the further development of effective therapeutic molecules.

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“…Another study established the importance of MARK4 in regulating biological processes, namely, glucose and energy homeostasis ( Sun et al, 2012 ). Thus, the aforementioned reports indicate that MARK4 is an attractive druggable target for cancers, neurodegeneration, and other disorders ( Anwar et al, 2022c ; Voura et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease

Adnan,

DasGupta,

Anwar

et al. 2023

Front. Pharmacol.

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Introduction: Hyperphosphorylation of tau is an important event in Alzheimer’s disease (AD) pathogenesis, leading to the generation of “neurofibrillary tangles,” a histopathological hallmark associated with the onset of AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) is an evolutionarily conserved Ser-Thr (S/T) kinase that phosphorylates tau and microtubule-associated proteins, thus playing a critical role in AD pathology. The uncontrolled neuronal migration is attributed to overexpressed MARK4, leading to disruption in microtubule dynamics. Inhibiting MARK4 is an attractive strategy in AD therapeutics.Methods: Molecular docking was performed to see the interactions between MARK4 and galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were performed to investigate the stability and conformational dynamics of the MARK4–GLT complex. We performed fluorescence binding and isothermal titration calorimetry studies to measure the binding affinity between GLT and MARK4. Finally, an enzyme inhibition assay was performed to measure the MARK4 activity in the presence and absence of GLT.Results: We showed that GLT, an acetylcholinesterase inhibitor, binds to the active site cavity of MARK4 with an appreciable binding affinity. Molecular dynamic simulation for 250 ns demonstrated the stability and conformational dynamics of the MARK4–GLT complex. Fluorescence binding and isothermal titration calorimetry studies suggested a strong binding affinity. We further show that GLT inhibits the kinase activity of MARK4 significantly (IC50 = 5.87 µM).Conclusion: These results suggest that GLT is a potential inhibitor of MARK4 and could be a promising therapeutic target for AD. GLT’s inhibition of MARK4 provides newer insights into the mechanism of GLT’s action, which is already used to improve cognition in AD patients.

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Synthesis, Structural Modification, and Bioactivity Evaluation of Substituted Acridones as Potent Microtubule Affinity-Regulating Kinase 4 Inhibitors

Cited by 5 publications

References 55 publications

Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis

Navigating the Maze of Kinases: CaMK-like Family Protein Kinases and Their Role in Atherosclerosis

Therapeutic targeting of microtubule affinity‐regulating kinase 4 in cancer and neurodegenerative diseases

Mechanistic insights into MARK4 inhibition by galantamine toward therapeutic targeting of Alzheimer’s disease

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