Targeting autophagy-related protein kinases for potential therapeutic purpose

Abstract

Autophagy, defined as a scavenging process of protein aggregates and damaged organelles mediated by lysosomes, plays a significant role in the quality control of macromolecules and organelles. Since protein kinases are integral to the autophagy process, it is critically important to understand the role of kinases in autophagic regulation. At present, intervention of autophagic processes by small-molecule modulators targeting specific kinases has becoming a reasonable and prevalent strategy for treating several varieties of human disease, especially cancer. In this review, we describe the role of some autophagy-related kinase targets and kinase-mediated phosphorylation mechanisms in autophagy regulation. We also summarize the small-molecule kinase inhibitors/activators of these targets, highlighting the opportunities of these new therapeutic agents.

Keywords: 4E-BP1, eukaryotic translation initiation factor 4E-binding protein; AKT1, AKT serine/threonine kinase 1; AMBRA1, autophagy/beclin-1 regulator 1; AMPK, AMP-activated protein kinase; ARF, auxin response factor gene; ATG, autophagy-related protein; Autophagy; Autophagy-related kinase; CaMKK2, calcium/calmodulin-dependent protein kinase kinase 2; DAPK, death associated protein kinase; FIP200, FAK family kinase-interacting protein of 200 kDa; GAP, GTPase-activating protein; GO, gene ontology; GSK3α, glycogen synthase kinase 3 alpha; HMGB1, high mobility group protein B1; Human disease therapy; JNK1, C-Jun N-terminal kinase; LC3, microtubule-associated protein 1 light chain 3; LKB1, serine/threonine-protein kinase stk11; LPS, lipopolysaccharide; LRRK2, leucine rich repeat kinase 2; PD, Parkinson's disease; PI, phosphatidylinositol; PI3 kinase, phosphoinositide 3-kinase; PI3P, phosphatidylinositol triphosphate; PIM2, proviral insertion in murine lymphomas 2; PINK1, PTEN-induced putative kinase 1; PIP2, phosphatidylinositol-4,5-bisphosphate; PKACα, a protein kinase cAMP-activated catalytic subunit alpha; PKCα, protein kinase C alpha type; PKD1, polycystin-1; PPIs, protein–protein interactions; PROTAC, proteolysis targeting chimeras; PTMs, post-translational modifications; Phosphorylation; Protein kinases; Rheb, the RAS homolog enriched in brain; Small-molecule kinase inhibitors/activators; TAK1, transforming growth factor activated kinase-1; TFEB, transcription factor EB; TNBC, triple-negative breast cancer; TSC1/2, tuberous sclerosis complex proteins 1/2; ULK complex, ULK1–mATG13–FIP200–ATG101 complex; ULK1, unc-51-like kinase 1; UVRAG, ultraviolet resistance-associated gene; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1.