Drug Discovery Opinion

The journal Nature Chemical Biology defines chemical biology as ‘both the use of chemistry to advance a molecular understanding of biology and the harnessing of biology to advance chemistry’.

Scientists at the Karolinska Institute, Stockholm, have exploited the principles of chemical biology in the study of apoptotic pathways. In a recent publication, the scientists identified a set of 40 chemical agents (‘bioprobes’) that induce apoptosis from screening of a chemical library.

Using a variety of reporter cell lines, they were able to establish that the ‘bioprobes’ induced different patterns of signalling. Experiments using a calcium chelator, BAPTAAM, showed that Ca²⁺ was involved in induction of apoptosis by the majority of the ‘bioprobes’ and that Ca²⁺ was in general required several hours into the apoptosis process. Further studies showed that the calmodulin pathway was an important mediator of the apoptotic response. Inhibition of calmodulin kinase II (CaMKII) resulted in more effective inhibition of apoptosis compared to inhibition of calpain, calcineurin/PP2B or DAP kinase. One of the ‘bioprobes’, the plant alkaloid helenalin, was used to study the role of CaMKII in apoptosis. Helenalin induced CaMKII, ASK1 and Jun-N-terminal kinase (JNK) activity, and inhibition of these kinases inhibited apoptosis.

The study shows that calcium signalling is generally not an early event during the apoptosis process and suggests that a CaMKII/ASK1 signalling mechanism is important for sustained JNK activation and apoptosis by some types of stimuli.

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