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The K252a Derivatives, Inhibitors for the PAK/MLK Kinase Family, Selectively Block the Growth of HAS Transformants

Nheu, Thao Va; He, Honga; Hirokawa, Yumikoa; Tamaki, Kazuhikob; Florin, Lorec; Schmitz, M. Lienhardc; Suzuki-Takahashi, Ikukod; Jorissen, Robert N.a; Burgess, Antony Wa; Nishimura, Susumud; Wood, Johnb; Maruta, Hiroshia

Original Article

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 pep-tide 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 inhibitors) 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.

aLudwig Institute for Cancer Research, PO Box 2008 Royal Melbourne Hospital, Parkville/Melbourne, Australia

bDepartment of Chemistry, Yale University, New Haven, Connecticut

cInstitute for Chemistry and Biochemistry, University of Bern, Bern, Switzerland

dBanyu Tsukuba Research Institute, Tsukuba, Ibaraki, Japan.

Reprint requests: Hiroshi Maruta, Ludwig Institute for Cancer Research, PO Box 2008 Royal Melbourne Hospital, Parkville/Melbourne, Australia 3050.

No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this article.

Received on February 4, 2002; accepted for publication March 20, 2002

© 2002 Lippincott Williams & Wilkins, Inc.