Diacylglycerol Signaling

46 P.M. Blumberg et al.
3.20 Conclusion
Reflecting their central role in cellular control, the families of signaling proteins
that integrate the information from the varying levels of DAG with that of other
second messengers and signaling pathways provide attractive opportunities for
drug development. Although cancer represents a major therapeutic target for these
proteins, their impact is as diverse as the underlying biology that they mediate
(DiazGranados and Zarate 2008; Chen and LaCasce 2008; Lee et al. 2008; Sun and
Alkon 2006; Churchill et al. 2008; Dempsey et al. 2007; Farhadi et al. 2006).
Because of the limited factors influencing specificity, largely encompassed by the
geometry of the catalytic site, kinase inhibitors represent one productive approach
for the PKCs and PKDs. The appreciably greater complexity of the C1 domain in
the context of the cellular environment poses a correspondingly greater challenge
for rational drug design. On the other hand, this complexity potentially provides the
basis for a level of specificity beyond that achievable with catalytic site inhibitors.
Moreover, the reality that only two of the classes of DAG receptors are protein
kinases means that standard strategies of enzymatic inhibitor design are not even available
for most of these other classes of targets. A critical theme in drug design is
that of whether a target is “druggable.” Here, the power of natural products asserts
itself. We know that the C1 domain is a druggable target because natural products,
designed by nature and acting through C1 domains, are in clinical trials. The challenge
is to build on this opportunity.
Acknowledgments This contribution was supported by the Intramural Research Program of the
NIH, National Cancer Institute, Center for Cancer Research.
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