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

Abstract

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.

Keywords: NF-κB; cancer; kinase inhibitors; mTOR signaling; microtubule affinity-regulating kinase 4; target therapy.