The K252a derivatives, inhibitors for the PAK/MLK kinase family selectively
block the growth of RAS transformants.
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.
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville,
Australia.
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.
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