Apoptosis, also known as programmed cell death or cellular suicide, is an intrinsic biological process without which the normal development of a multicellular organism is impossible [1]. This process is strictly controlled to ensure the normal functioning and development of organismal tissues, the immune response, and the elimination of damaged or old cells [2].
Proteins involved in human apoptosis are an important therapeutic target. For example, cancer cells often acquire mutations or alterations in genes that regulate the apoptotic pathway, leading to impaired cell death and uncontrolled cell proliferation [3]. Also, many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are associated with the accumulation of misfolded proteins and neuronal cell death. Apoptosis can be triggered by the aggregation of these proteins and the activation of apoptotic signaling pathways. The death of neurons contributes to these diseases' progression and associated symptoms [4]. Apoptosis is involved in the development of various cardiovascular diseases, including heart failure, atherosclerosis, and myocardial infarction. Cardiomyocytes undergo apoptosis in response to ischemic injury, oxidative stress, and other pathological stimuli. Excessive cardiomyocyte death can lead to myocardial and cardiac dysfunction [5-6].
The Life Chemicals team has developed this new Screening Library of over 26,800 drug-like compounds potentially targeting proteins of the apoptotic signaling pathway to provide a new effective tool for apoptosis-related drug discovery.
Fig. 1. Morphological changes of an animal cell are induced by apoptosis and pro-apoptotic proteins that contribute to these changes at the respective stages of apoptosis.
Legend: FasL - Apoptosis antigen ligand; TRAIL - Tumor necrosis factor receptor; TNF-α - Tumor necrosis factor ligand superfamily member 13; Bcl-2 - Apoptosis regulator Bcl-2; BAK - Bcl-2 homologous antagonist/killer; Casp8 - Caspase 8; Casp9 - Caspase 9; COX - Cytochrome c oxidase; APAF-1 - Apoptotic protease-activating factor 1; ROCK - Rho-associated protein kinase; PARP-1 - Poly [ADP-ribose] polymerase 1; DFF - DNA fragmentation factor.
Fig. 2. The process of apoptosis in a plant cell and morphological changes induced by pro-apoptotic plant proteins.
Legend: PS - Piperine synthase; NO - Nitric oxide synthase; AOX - Ubiquinol oxidase; VEIDase - Caspase-like protein; YVAD - Caspase 1 inhibitor; PARPs - Poly [ADP-ribose] polymerase; PCD - Probable pterin-4-alpha-carbinolamine dehydratase, chloroplastic; SAR - Protein SAR; SnRK1 - SNF1-related protein kinase catalytic subunit alpha KIN11; SINAT - Putative E3 ubiquitin-protein ligase SINAT; ATG6 - Beclin-1-like protein.
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Compound selection
The reference set of reported molecules involved in apoptosis was obtained from the ChEMBL database. This set included all available compounds with high experimental activity against targets of apoptotic pathways. A two-dimensional fingerprint similarity search was performed against the Life Chemicals HTS Compound Collection using a Tanimoto index threshold of ≥ 0.85. To further refine the compound selection, PAINS and reactive groups were removed by means of in-house developed medchem filters.
The resulting Screening Set comprises over 26,800 structurally diverse screening compounds related to apoptotic pathways. Among the selected screening molecules there are promising inhibitors of the following molecular targets associated with apoptosis pathways:
- 15-hydroxyprostaglandin dehydrogenase [NAD+]
- 3-phosphoinositide dependent protein kinase-1
- Adenosine receptor A1, A2a
- Adrenoceptor beta 3
- Amino acid transporter
- Anoctamin-1
- Apoptotic protease-activating factor 1
- Bcl2-antagonist of cell death (BAD)
- Bcl-2-related protein A1
- Bis(5'-adenosyl)-triphosphatase
- Caspase-3, 6, 7
- Cellular tumor antigen p53
- Cyclic AMP-dependent transcription factor ATF-6 alpha
- Delta(3,5)-Delta(2,4)-dienoyl-CoA isomerase, mitochondrial
- Deoxynucleoside triphosphate triphosphohydrolase SAMHD1
- Dual specificity tyrosine-phosphorylation-regulated kinase 1A, 1B, 3
- Fibrinogen beta chain
- Fibrinogen C domain-containing protein 1
- Galactocerebrosidase
- Immunoglobulin lambda variable 6-57
- Induced myeloid leukemia cell differentiation protein Mcl-1
- MDM2-MDMX
- Microphthalmia-associated transcription factor
- NADPH oxidase 1
- Neurotrophic tyrosine kinase receptor type 2
- 26S proteasome non-ATPase regulatory subunit 14
- P2X purinoceptor 1, 7
- p53-binding protein Mdm-2
- Peripheral myelin protein 22
- Poly [ADP-ribose] polymerase-1
- Protein-tyrosine phosphatase 1B, 1C, 2C
- Retinoblastoma-associated protein
- Retinoic acid receptor beta
- Rho-associated protein kinase 1, 2
- Serine/threonine-protein kinase RIPK2
- Signal transducer and activator of transcription 1-alpha, beta, 3
- Sodium-dependent neutral amino acid transporter B(0)AT2
- Succinate dehydrogenase [ubiquinone] flavoprotein subunit / iron-sulfur subunit, mitochondrial
- Telomerase reverse transcriptase
- Transcription factor GATA-4, p65
- Transcriptional coactivator YAP1
- Transcriptional enhancer factor TEF-3
- Tumor necrosis factor ligand superfamily member 10
- Tyrosine-protein kinase ABL, BRK, FYN, JAK2, JAK3, LCK, SYK, YES, 2 beta
- Tyrosine-protein kinase receptor FLT3, RET, TYRO3, UFO
Representative screening compounds from the Apoptosis Signaling Pathway Screening Library
References:
- Bertheloot D, Latz E, Franklin BS. Necroptosis, pyroptosis, and apoptosis: an intricate game of cell death. Cell Mol Immunol. 2021;18(5):1106-1121. doi:10.1038/s41423-020-00630-3
- D'Arcy MS. Cell death: a review of the major forms of apoptosis, necrosis, and autophagy. Cell Biol Int. 2019;43(6):582-592. doi:10.1002/cbin.11137
- Morana O, Wood W, Gregory CD. The Apoptosis Paradox in Cancer. Int J Mol Sci. 2022 Jan 25;23(3):1328. doi: 10.3390/ijms23031328. PMID: 35163253; PMCID: PMC8836235.
- Erekat NS. Apoptosis and its therapeutic implications in neurodegenerative diseases. Clin Anat. 2022 Jan;35(1):65-78. doi: 10.1002/ca.23792. Epub 2021 Oct 7. PMID: 34558138.
- Goldblatt ZE, Cirka HA, Billiar KL. Mechanical Regulation of Apoptosis in the Cardiovascular System. Ann Biomed Eng. 2021 Jan;49(1):75-97. doi: 10.1007/s10439-020-02659-x. Epub 2020 Nov 9. PMID: 33169343; PMCID: PMC7775273.
- Shan R, Liu N, Yan Y, Liu B. Apoptosis, autophagy, and atherosclerosis: Relationships and the role of Hsp27. Pharmacol Res. 2021 Apr;166:105169. doi: 10.1016/j.phrs.2020.105169. Epub 2020 Oct 11. PMID: 33053445.