Abstract
Microtubule affinity regulating kinase 4 (MARK4) is a Ser/Thr kinase, considered as a potential drug target for cancer, diabetes and neurodegenerative diseases. Due to its significant role in the development and progression of cancer, different in-house libraries of synthesized small molecules were screened to identify potential MARK4 inhibitors. A small library of hydrazone compounds showed a considerable binding affinity to MARK4. The selected compounds were further scrutinized using an enzyme inhibition assay and finally two hydrazone derivatives (H4 and H19) were selected that show excellent inhibition (nM range). These compounds have a strong binding affinity for MARK4 and moderate binding with human serum albumin. Anticancer studies were performed on MCF-7 and A549 cells, suggesting H4 and H19 selectively inhibit the growth of cancer cells. The IC50 value of compound H4 and H19 was found to be 27.39 μM and 34.37 μM for MCF-7 cells, while for A549 cells it was 45.24 μM and 61.50 μM, respectively. These compounds inhibited the colonogenic potential of cancer cells and induced apoptosis. Overall findings reflect that hydrazones/hydrazone derivatives could be exploited as potential lead molecules for developing effective anticancer therapies via targeting MARK4.
Highlights
Protein kinases catalyze the transfer of phosphate from ATP to Ser/Thr/Tyr side chains of speci c target proteins to induce conformational changes and subsequent modulation in their activities.[1]
We have screened a small library of hydrazone derivatives that shows a signi cant binding affinity with the Microtubules affinity regulated kinase 4 (MARK4)
The results of screening and docking are shown in the Electronic supplementary information (ESI) Fig. S1–S4.† Docking results suggested that selected molecules signi cantly bind with active site residues of MARK4
Summary
Protein kinases catalyze the transfer of phosphate from ATP to Ser/Thr/Tyr side chains of speci c target proteins to induce conformational changes and subsequent modulation in their activities.[1]. Phosphorylation of conserved threonine residue (Thr214) by Liver Kinase B1 (LKB1) and MARKK/TAO-1 (MARK Kinase/ Thousands and One amino acids) in the activation loop activates MARK4, while phosphorylation in Ser[218] residue inactivates.[18] MARK4 is a primary regulator of Wnt signaling pathway and high expression is linked with Wnt-induced prostate cancer, providing as a signi cant target for the development of anti-cancer drugs.[19] The inhibition of MARK4 suppresses the progression of glioma.[20] Many potential natural and synthetic molecules have been identi ed as MARK4 inhibitors.[9,21,22,23,24,25,26,27] These inhibitors decrease the growth and proliferation of different cancer cell types and indicate the importance of MARK4 inhibitors to improve the outcomes of associated cancers. Our results show the potential of hydrazone derivatives for the development of anticancer molecules which may be further exploited for clinical management of anticancer therapy
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