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Nheu TV, He H, Hirokawa Y, Tamaki K, Florin L, Schmitz ML, Suzuki-Takahashi I,
Jorissen RN, Burgess AW, Nishimura S, Wood J, Maruta H.
The K252a derivatives, inhibitors for the PAK/MLK kinase family selectively
block the growth of RAS transformants.
Cancer J. 2002 Jul-Aug;8(4):328-36.
BACKGROUND: Oncogenic RAS mutants such as v-Ha-RAS activate
members of Rac/CDC42-dependent kinases (PAKs) and appear to
contribute to the development of more than 30% of all human
cancers. PAK1 activation is essential for oncogenic RAS
transformation, and several chemical compounds that inhibit Tyr
kinases essential for the RAS-induced activation of PAK1
strongly suppress RAS transformation either in cell culture or
in vivo (nude mice). Although we have developed a cell-permeable
PAK-specific peptide inhibitor called WR-PA18, so far no
chemical (metabolically stable) compound has been developed that
directly inhibits PAK1 in a highly selective manner. Thus, we
have explored such a PAK1 inhibitor(s) among synthetic
derivatives of an adenosine triphosphate antagonist.
RESULTS: From the naturally occurring adenosine triphosphate
antagonist K252a, we have developed two bulky derivatives,
called CEP-1347 and KT D606 (a K252a dimer), which selectively
inhibit PAKs or mixed-lineage kinases both in vitro and in cell
culture and convert v-Ha-RAS-transformed NIH 3T3 cells to flat
fibroblasts similar to the parental normal cells. Furthermore,
these two K252a analogues suppress the proliferation of v-Ha-RAS
transformants, but not the normal cells.
CONCLUSION: These bulky adenosine triphosphate antagonists
derived from K252a or related indolocarbazole compounds such as
staurosporine would be potentially useful for the treatment of
RAS/ PAK1-induced cancers, once their anti-PAK1 activity is
significantly potentiated by a few additional chemical
modifications at the sugar ring suggested in this paper.
PMID: 12184411 |
