Drug Discovery in Apoptosis


Regulation of cell death (apoptosis) is a crucial process that has to be precisely modulated during normal cell growth, and inappropriate regulation of this process has been implicated in a large number of ailments ranging from cancer to neurodegenerative diseases. Given that apoptosis can be either induced (e.g. following tissue injury or ischaemia) or attenuated (e.g. in cancer), there are a large number of potential intervention strategies that can be taken. To date, there are no approved therapeutics whose primary mode of action involves modulation of a critical component of the apoptotic pathway. However, there is an increasing number of therapeutics that are actively being tested in clinical trials, some of which are likely to become approved therapeutics.

Key Concepts

  • Caspases are implicated as potential therapeutic targets in a large number of clinically relevant indications.

  • Small molecule caspase inhibitors can be identified, but developing these into therapeutic drugs has proven to be very challenging.

  • There are many liabilities associated with caspase inhibitors, such as the warhead (reversible or irreversible), the apparent near absolute requirement for a P1 aspartic acid and selectivity.

  • So far, only one of the four caspase inhibitors that have entered clinical trials is still being actively developed, the remaining three have been discontinued for a variety of reasons.

  • Novel approaches to drug discovery can be taken; for example, utilizing a novel allosteric site that many caspases appear to contain.

  • There are a number of additional targets in the apoptotic pathway that are therapeutically relevant.

Keywords: caspase inhibitor; apoptosis; inflammation

Figure 1.

Anatomy of an active site caspase inhibitor. (a) Generalized structure with the three key regions highlighted. (b) Examples of different warheads. (c) Two examples of inhibitors that lack a P1 aspartic functionality. (d) Examples of caspase inhibitors with associated inhibitory activity. (e) Two caspase inhibitors that were derived from a fragment‐based discovery approach. The initial fragments that were identified from screening are highlighted with a dashed line, and these fragments were subsequently linked to an aspartic acid and warhead to generate a fully elaborated molecule.

Figure 2.

Differences in the conformation of the caspase‐1 active site either when crystallized in the absence of a ligand (PDB 1SC1), in the presence of malonate (PDB 1SC3) or in the presence of a peptide inhibitor (PDB 1ICE). The residue in blue and outlined by a dashed line is the active site cysteine residue, and the critical Arg341 (in red) and loop 3 are indicated.

Figure 3.

Caspase inhibitors that have entered clinical trials.

Figure 4.

The structure of caspase‐7 either with an allosteric site inhibitor (PDB 1SHJ) or with a peptide active site inhibitor bound (PDB 1F1J). The dashed box contains the allosteric binding site. The critical Arg187 that forms part of the S1 pocket is shown in red, and is displaced from the allosteric site when the DICA compound is bound (left panel). This residue occupies the allosteric pocket when the active site is occupied with a tetrapeptide inhibitor (DEVD‐CHO) (right panel), thus preventing binding of DICA.



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Further Reading

LaCasse EC, Mahoney DJ, Cheung HH et al. (2008) IAP‐targeted therapies for cancer. Oncogene 27: 6252–6275.

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O'Brien T and Linton SD (2009) Design of Caspase Inhibitors as Potential Clinical Agents. CRC Enzyme Inhibitors Series. Boca Raton, FL: CRC Press.

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O'Brien, Tom, and Dixit, Vishva M(Dec 2009) Drug Discovery in Apoptosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021587]