Autophagy is a naturally regulated mechanism of the cell that disassembles unnecessary or dysfunctional components, contributing to maintaining cell and body homeostasis [1]. Disturbance of autophagy mechanisms or an excessive autophagic flow can lead to cell death. Defective autophagy provokes a number of diseases, such as cancer, cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular diseases [2]. The interplay between autophagy and apoptosis affects the development and course of numerous rheumatic diseases [3].
In light of the above, targeting autophagic pathways has turned out to become a promising strategy in drug discovery, as both enhancing and inhibiting autophagy can create therapeutic opportunities in treating cancer, neurodegenerative diseases, infectious diseases, and cardiac ischemia.
Life Chemicals has prepared a proprietary Autophagy-focused Screening Library of more than 6,200 autophagy-associated screening compounds, including but not limited to predicted mTOR, PI3K inhibitors, apoptosis regulators, ROS and AMPK modulators, and other relevant protease and kinase inhibitors. This Screening Set of autophagy pathway-related compounds is aimed at high throughput screening (HTS) and drug discovery projects focused on autophagy, anticancer and antiinflammatory research.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Background information
Autophagy, cellular senescence, and apoptosis, correlating with each other, are three key responses of a cell facing stress. During autophagy, targeted misfolded proteins and damaged cytoplasmic organelles are isolated from the rest of the cell within a double-membraned vesicle known as an autophagosome. The autophagosome eventually fuses with lysosomes, with the contents being degraded and recycled. Autophagy performs a wide variety of physiological and pathophysiological roles. Noteworthy, it has been reported that defects of autophagy are associated with genomic damage, metabolic stress, tumorigenesis, neurodegeneration, aging, and heart disease.
In cancer, autophagy can play a dual role: it can initially suppress tumor formation by eliminating damaged organelles and proteins; however, in developed tumors, it may instead support cancer cell survival during periods of stress. Neurodegenerative diseases, like Alzheimer's and Parkinson's, are linked to dysfunctional autophagy, resulting in the buildup of harmful protein aggregates. Up-regulating autophagy can help eliminate intracellular pathogens in infectious diseases, strengthening the body's defense. However, strategic down-regulation may be required when pathogens exploit the autophagic machinery for survival. In cardiovascular diseases, particularly coronary heart disease, autophagy is also seen to be a twofold factor. Up-regulation can aid in removing damaged cellular components post-ischemia, protecting cardiac cells. Conversely, controlled down-regulation may be necessary to prevent excessive autophagic cell death during reperfusion.
Figure 1. Central mechanisms of autophagy regulation and potential drug targets.
Compound selection
A reference set of molecules with a defined autophagy-inducing or -inhibitory activity was first prepared based on the ChEMBL database (IC50, Ki, etc., less than 10 μM, Inhibition > 25%). Subsequently, a 2D fingerprint similarity analysis with a Tanimoto index ≥ 0.75 was performed against the Life Chemicals HTS Compound Collection.
As a result, we picked out around 6,200 small-molecule screening compounds potentially effective against the following autophagy-related protein targets:
- AMPK alpha1,2/beta1,2/gamma1,3
- PI3-kinase p110-alpha, beta, delta, gamma subunits
- Cysteine protease ATG4B
- Apoptosis regulator BAX, Bcl-2, Bcl-W, Bcl-X
- Bcl-2-related protein A1
- Serine/threonine-protein kinase ULK1
- Proto-oncogene tyrosine-protein kinase ROS
- Ras-related protein Rab-7a
- Phosphatidylinositol 3-kinase catalytic subunit type 3
- Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing beta polypeptide
- mTORC1
- PI3-kinase p85-alpha subunit
- Bcl2-antagonist of cell death (BAD)
- Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing subunit alpha
- Bcl-2-like protein 10
- Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
It should be stressed that the Screening Set of these potential inhibitors and inducers of autophagy was not narrowed down by structural and physicochemical parameters in order not to avoid filtering out potential inhibitors. Customized compound selection and parameter filtering are available on request and will depend on the guidelines of the drug discovery project in question.
Figure. 2. Target distribution in the Life Chemicals Autophagy Screening Compound Library.
Representative screening compounds from the Autophagy-focused Screening Library
Reference:
- Liu S, Yao S, Yang H, Liu S, Wang Y. Autophagy: Regulator of cell death. Cell Death Dis. 2023;14(10):648. Published 2023 Oct 4. doi:10.1038/s41419-023-06154-8.
- Klionsky DJ, Petroni G, Amaravadi RK, et al. Autophagy in major human diseases. EMB J.2021;40(19):e108863. doi:10.15252/embj.202110886.
- Sorice M. Crosstalk of Autophagy and Apoptosis. Cells. 2022;11(9):1479. Published 2022 Apr 28. doi:10.3390/cells11091479.