Homework SourseWhat molecule would you target if asked to design an apoptot
Solution
Answer:
The most obvious apoptotic target is selective activation of caspases. Procaspase-3, the proenzyme of a key effector substrate is inhibited by intramolecular interactions facilitated by 3 asp residues, designated as the \'safety catch\'. Screening for small molecules can be performed to interfere with this intramolecular conformation of procaspase-3 (A direct approach).
The activation of caspase by an indirect approach can also be useful. XIAP is an endogenous caspase inhibitor overexpressed in many cancer cells. An inhibitor of XIAP, polyphenylurea directly relieves the inhibition of caspase-3 and caspase-7. These small molecule inhibitors binds to the XIAP domain known to interact and block the active site of caspase-3 and caspase-7. These compounds induce apoptosis in a wide range of cancer cell lines and shows antitumor activity in animal tumor models.
Targeted anticancer drugs are designed to bind with specific targets with the goal of suppressing tumor growth. The hope is that these drugs will be more selective than hormones and cytotoxic anticancer drugs, and hence will be able to destroy cancer cells while leaving normal cells untouched. A few targeted drugs, such as imatinib, have been remarkably successful, producing complete responses with relatively mild adverse effects. Unfortunately, with many other targeted drugs, responses have been less impressive, while adverse effects have been more severe.
The administration of recombinant human TRAIL ligand has exhibited promising antitumor activity in animal models. But, it can result in hepatic toxicity due to TRAIL induced apoptotic response found to occur in human hepatocytes in culture.
Nonetheless, the concept of targeted therapy has great appeal, and intensive research is underway to make it more of a reality.
