Novel pharmacological modulators of autophagy: an updated patent review (2012-2015)

ABSTRACT

Introduction: Autophagy is a lysosome-dependent degradation pathway that maintains cellular homeostasis in response to a variety of cellular stresses. Accumulating reports based on animal models have indicated the importance of this catabolic program in many human pathophysiological conditions, including diabetes, neurodegenerative diseases, aging, and cancers. Therefore, autophagy has been highlighted as a novel therapeutic target with a wide range of beneficial effects on human diseases. Here, we review the recent advances of our knowledge toward autophagy, as well as the efforts for developing autophagy modulators.

Areas covered: The relevant patents (published at 2012–2015) and the research literature claiming the pharmacological modulation of autophagy are reviewed. Also, their molecular mechanisms and potential therapeutic utilities are discussed.

Expert opinion: Considering the molecular machinery involved in autophagy induction, the targeting of autophagy-specific protein is very important to design the therapeutic interventions for specifically treating a variety of autophagy-associated disorders. Many patents and the research literature described in this review have shown promising applications of the relevant autophagy modulators for cancer or neurodegeneration treatments, a few of which are already being considered for clinical evaluation. However, most patents have claimed the modulators of autophagy with little information regarding their mechanisms of action. To design highly potent therapeutics, further work, such as developing compounds that specifically target the autophagy-specific machinery, are required.

KEYWORDS:

• Autophagy
• autophagy modulators
• AMPK/mTORC1
• ULK1
• PIK3C3/VPS34
• Beclin 1
• neurodegenerative diseases
• cancer

Article highlights

• Autophagy is a lysosome-dependent catabolic pathway required for cellular homeostasis to recycle the degradative materials for either the source of energy or the building blocks for the synthesis of new macromolecules.

• Dysfunction of autophagy has been implicated in a wide range of physiological conditions ranging from adaptation to starvation, cell differentiation/development/death, organelle homeostasis, tumor suppression, immunity, and aging. Therefore, modulation of autophagy may provide additional opportunity to discover the novel therapeutic methods for the relevant human diseases.

• Most patents covered in this review have claimed the modulators of autophagy with little information about the mechanism of actions. Further works are required to design the compounds that selectively modulate autophagy at many different conditions for the therapeutic use in a variety of autophagy-related diseases.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by grants from Korean Health Technology R&D project (HI14C2700 to J Ha) and the National Research Foundation of Korea (NRF) (MEST, No 2015R1D1A1A01059401 and No 2012M3A9C6049935 to J Kim).