Natural Products as Autophagy-related Protein Kinase Inhibitors: A Future Promising Anticancer from Nature

Autophagy plays a vital role in maintaining cellular homeostasis, and its dysregulation is closely associated with cancer progression. Targeting autophagy-related protein kinases has emerged as a promising therapeutic approach.

This review analyzes studies retrieved from the PubMed database to identify natural products with inhibitory activity against autophagy-related protein kinases.

Plant-derived secondary metabolites, including polyphenols, alkaloids, terpenoids, and flavonoids, were identified as modulators of key autophagy-related kinases such as mTOR, AMPK, ULK1, and Beclin-1. These compounds regulate autophagy by influencing signaling pathways that control autophagosomal formation and degradation, thereby affecting cancer cell survival. They originate from diverse plant parts (such as leaves, seeds, and rhizomes) and exhibit activity across various cancer types, including hepatic, breast, lung, colorectal, gastric, and brain malignancies.

Although these natural compounds showed significant anticancer potential, challenges such as poor bioavailability and limited pharmacokinetics persist. Advances in nano-formulations, structural modifications, and structure-activity relationship-guided optimization have improved their efficacy.

Overall, natural products targeting autophagy-related kinases hold great promise as leads for novel anticancer agents, warranting further in vivo validation, pharmacological optimization, and synergistic studies as adjuncts.