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This special issue of Cellular & Molecular Biology Letters presents the Abstracts of Invited Lectures, and of submitted accepted posters (several of
which have been selected for short oral presentation) to the 4th International
Conference on INHIBITORS OF PROTEIN KINASES (IPK'2005), to take
place in Warsaw, Poland, June 25-29, 2005. Also included are Abstracts of
several invited lectures, and submitted posters, at an associated Workshop on
"Modelling of Specific Molecular Recognition Processes", and relevance to
protein kinases.
Protein phosphorylation is widely recognized as the most important pathway for
regulation of protein functions in living cells, by switching cellular activities
from one state to another and, in this way, regulating gene expression, cell
proliferation and differentiation. It is the major mechanism whereby cells
respond to extracellular signals, such as hormones and growth factors, thus
controlling all events at various stages of the cell cycle, as well as the response
of the cell to environmental and nutritional stress. Reversible protein
phosphorylation is catalyzed by the interplay between protein kinases and
protein phosphatases.
Given the key role of protein kinases in signal transduction, it was to be
anticipated that this would stimulate searches for inhibitors. But, in striking
contrast to other enzyme systems, more than 500 protein kinases have now been
identified in the human genome alone, all of them catalyzing a similar reaction.
It would therefore appear to be a formidable task to develop potent, selective,
and cell-permeable, inhibitors for a given kinase. However, a variety of
sophisticated approaches, both experimental and theoretical, directed towards
this goal have resulted in remarkable progress, as will be seen from the Abstracts
in a session on this subject. Notwithstanding the fact that most of them are ATPcompetitive,
it is clear that subtle differences in the unique conformations of the
catalytic pockets (conformational flexibility, induced fit) play a key role in
determining selectivity. Many relatively selective inhibitors are now routinely
employed in experiments designed to delineate signal transduction pathways. In
this context, it is worth noting, as pointed out recently by Doriano Fabbro of
Novartis [Assays & Drug Develop. Technol. 2 (2004) 2-6], that "availability of a
good lead (compound) is the key to successful optimization and is much more
important than the availability of a structure of the target". This is in line with
our own experience in the initial development of tetrabromo- benzotriazole and
benzimidazole selective cell-permeable inhibitors of protein kinase CK2 from
various sources. But, once a good lead compound has been identified, by
whatever means, subsequent structure-based design for further optimization has
decisively demonstrated its merits.
Furthermore, it has long been known that dysfunctions in activities of protein
kinases (and phosphatases) may lead to severe pathological states. It is
consequently not surprising that the Biotechnology sector, frequently in
collaboration with Academia, is presently devoting major efforts (30 - 40% of their research budgets) to "targeting" protein kinases for drug development, with
considerable achievements to date, Gleevec being a prime, but by no means the
only, example. It is, consequently, most appropriate that, as at previous IPK
meetings, participants at the present Conference include representatives of some
major Biotechnology firms actively engaged in this field.
A novel feature of the 3rd International Conference (IPK'2003) was a special
session on the newly emerging field of protein kinases of pathogenic agents such
as viruses, parasites and fungi. Bearing in mind current world-wide efforts to
cope with diseases such as malaria (which alone is responsible for more than 1
million deaths annually), caused by protozoan parasites, the present Conference
includes a special session on the protein kinases of parasitic protozoa, as well as
of their host cells, and accompanying efforts to develop inhibitors of these
enzymes as therapeutic agents.
Another field that is slowly coming to the forefront is that of histidine kinases of
the two-component type, hitherto well characterized in bacteria, plants and
fungi. There is now compelling evidence for such enzymes in mammalian cells,
and two speakers at this meeting will present up-to-date reviews on what is
known about histidine kinases and histidine phosphatases in mammalian
systems.
We wish to express our appreciation to members of the International Advisory
Board for assistance in organizing the program and, in particular, to Christian
Doerig and Laurent Meijer for their help in preparing the sessions on parasite
kinases and selective kinase inhibitors, respectively. We are indebted to most of
the contributors to this Conference, who have complied with our request for
Abstracts that are informative, including key references; and to Barbara Kleyny
of the IPK Secretariat for her unstinting efforts in checking their conformity with
the requirements of the journal.
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