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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.