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Introduction
It is the beauty of nature that it keeps a check on each and every reaction taking place within us. There is a discipline not only in the creation of newer entities but there is also decency in the destruction of older ones when not required. The programmed destruction of cells is called as apoptosis. Any disturbance in the onset or process of apoptosis can lead to serious diseases including cancer. Various types of cancers to date have been reported to be associated with problems which inhibit the apoptotic pathways. This facilitated the need of designing compound libraries that contain apoptosis promoting drugs. Such drugs have the ability to inhibit cell division thereby preventing tumor production and metastasis.
The Process of Apoptosis
Apoptotic pathways are broadly classified as intrinsic and extrinsic apoptotic pathways. Extrinsic pathway is activated when extracellular death ligands like TNF ligand or TNF related apoptosis inducing ligand (TRAIL) bind to the death receptors. This binding stimulates the downstream signaling cascade. Fas associated death domain is recruited followed by the procaspase 8 which is activated to caspase 8. This stimulates caspase3/7 which finally induces apoptosis. Intrinsic pathway is stimulated by chemotherapy or radiotherapy. This pathway derives the p53 mediated activation of Smac and caspase-9 which further stimulate caspase-3/7 thereby stimulating apoptosis. Sometimes, there is a cross talk between intrinsic and extrinsic pathways through caspase 8 mediated proteolysis of BID. Apoptosis inhibitors proteins (IAPs) are the keys in preventing the cellular suicide. IAPs inhibit caspae-3, caspase-7 and caspase-9. However, Smac mimetics bind IAPs and promote apoptosis as shown in the following figure [1]. Nature maintains a balance between the expression of apoptosis promoting and inhibiting factors to prevent diseases like cancer.
Targets in Apoptosis
Based on the information of apoptotic pathways, certain molecular targets [2] have been highlighted which can be exploited to design drugs. When the targets are highlighted, it becomes easier to rationally design inhibitors against those specific targets instead of blindly following the screening processes.
Death Receptors (TRAIL Receptors, CD95/Fas, TNF)
Caspases (Pan-caspase, caspase-1, caspase-3, caspase-6, caspase-9)
IAPs and Smac
Survivin
Bcl-2 proteins (Antiapoptotic Bcl-2 members, Pro-apoptotic Bcl-2 members)
p53
Apoptosis inducers versus inhibitors
Some of the diseases need apoptosis inhibitors for their cure, e.g. cancer is the abnormal growth of cells. Apoptosis induction ion these cells can prevent the spread of disease. Several apoptosis inducers are available in the compound libraries including belinostat, vorinostat etc.
There are some diseases which need inhibition of apoptosis for example myocardial infarction, sepsis, stroke, liver diseases etc. These scenarios induce the production of ¡®caspases¡¯ which lead to apoptosis in damaged tissues. Apoptosis inhibitors are used as drugs in these cases to prevent tissue damage in sensitive organs like brain, liver or heart etc. Inhibitors like VX-765 are available in compound libraries to circumvent apoptosis.
Cancer Drugs as Apoptosis Inducers
Also, many important cancer drugs are known to promote apoptosis thereby inhibiting uncontrolled cell division. Following figure [3]gives an idea of the importance of apoptosis promoting, anticancer drugs like imatinib, trastuzumab, gefitinib, bortezomib (velcade), cetuximab and bevacizumab in the drug market. Golden coins refer to sales of drugs in US$ millions in 2003 while blue bars show the sale in US$ millions in 2004.
Conclusion
In a nutshell, apoptosis targeting compound libraries are highly beneficial for cancer research and drug discovery. Apoptosis is an important target whose regulation can prevent the prevalence of cancer and other diseases. The process of apoptosis is an interesting target for compounds in chemical libraries as both inhibition and induction of this process finds its application in pharmaceutical industry. Compound libraries provide a variety of compounds which can be used to induce or inhibit apoptosis thereby inhibiting uncontrolled cell division and preventing tissue damage!
To meet customers's needs and satisfaction, our purpose is to provide scientists world-wide an easy access to the most innovative life science reagents like Fostamatinib, Panobinostat, AUY922 and to help them make more significant discoveries.
It is the beauty of nature that it keeps a check on each and every reaction taking place within us. There is a discipline not only in the creation of newer entities but there is also decency in the destruction of older ones when not required. The programmed destruction of cells is called as apoptosis. Any disturbance in the onset or process of apoptosis can lead to serious diseases including cancer. Various types of cancers to date have been reported to be associated with problems which inhibit the apoptotic pathways. This facilitated the need of designing compound libraries that contain apoptosis promoting drugs. Such drugs have the ability to inhibit cell division thereby preventing tumor production and metastasis.
The Process of Apoptosis
Apoptotic pathways are broadly classified as intrinsic and extrinsic apoptotic pathways. Extrinsic pathway is activated when extracellular death ligands like TNF ligand or TNF related apoptosis inducing ligand (TRAIL) bind to the death receptors. This binding stimulates the downstream signaling cascade. Fas associated death domain is recruited followed by the procaspase 8 which is activated to caspase 8. This stimulates caspase3/7 which finally induces apoptosis. Intrinsic pathway is stimulated by chemotherapy or radiotherapy. This pathway derives the p53 mediated activation of Smac and caspase-9 which further stimulate caspase-3/7 thereby stimulating apoptosis. Sometimes, there is a cross talk between intrinsic and extrinsic pathways through caspase 8 mediated proteolysis of BID. Apoptosis inhibitors proteins (IAPs) are the keys in preventing the cellular suicide. IAPs inhibit caspae-3, caspase-7 and caspase-9. However, Smac mimetics bind IAPs and promote apoptosis as shown in the following figure [1]. Nature maintains a balance between the expression of apoptosis promoting and inhibiting factors to prevent diseases like cancer.
Targets in Apoptosis
Based on the information of apoptotic pathways, certain molecular targets [2] have been highlighted which can be exploited to design drugs. When the targets are highlighted, it becomes easier to rationally design inhibitors against those specific targets instead of blindly following the screening processes.
Death Receptors (TRAIL Receptors, CD95/Fas, TNF)
Caspases (Pan-caspase, caspase-1, caspase-3, caspase-6, caspase-9)
IAPs and Smac
Survivin
Bcl-2 proteins (Antiapoptotic Bcl-2 members, Pro-apoptotic Bcl-2 members)
p53
Apoptosis inducers versus inhibitors
Some of the diseases need apoptosis inhibitors for their cure, e.g. cancer is the abnormal growth of cells. Apoptosis induction ion these cells can prevent the spread of disease. Several apoptosis inducers are available in the compound libraries including belinostat, vorinostat etc.
There are some diseases which need inhibition of apoptosis for example myocardial infarction, sepsis, stroke, liver diseases etc. These scenarios induce the production of ¡®caspases¡¯ which lead to apoptosis in damaged tissues. Apoptosis inhibitors are used as drugs in these cases to prevent tissue damage in sensitive organs like brain, liver or heart etc. Inhibitors like VX-765 are available in compound libraries to circumvent apoptosis.
Cancer Drugs as Apoptosis Inducers
Also, many important cancer drugs are known to promote apoptosis thereby inhibiting uncontrolled cell division. Following figure [3]gives an idea of the importance of apoptosis promoting, anticancer drugs like imatinib, trastuzumab, gefitinib, bortezomib (velcade), cetuximab and bevacizumab in the drug market. Golden coins refer to sales of drugs in US$ millions in 2003 while blue bars show the sale in US$ millions in 2004.
Conclusion
In a nutshell, apoptosis targeting compound libraries are highly beneficial for cancer research and drug discovery. Apoptosis is an important target whose regulation can prevent the prevalence of cancer and other diseases. The process of apoptosis is an interesting target for compounds in chemical libraries as both inhibition and induction of this process finds its application in pharmaceutical industry. Compound libraries provide a variety of compounds which can be used to induce or inhibit apoptosis thereby inhibiting uncontrolled cell division and preventing tissue damage!
To meet customers's needs and satisfaction, our purpose is to provide scientists world-wide an easy access to the most innovative life science reagents like Fostamatinib, Panobinostat, AUY922 and to help them make more significant discoveries.
