The K252a derivatives, inhibitors for the PAK/MLK kinase family, selectively block the growth of RAS transformants

Thao V. Nheu, Hong He, Yumiko Hirokawa, Kazuhiko Tamaki, Lore Florin, M. Lienhard Schmitz, Ikuko Suzuki-Takahashi, Robert N. Jorissen, Antony W. Burgess, Susumu Nishimura, John Wood, Hiroshi Maruta

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)328-336
Number of pages9
JournalCancer Journal
Issue number4
Publication statusPublished or Issued - 1 Aug 2002
Externally publishedYes


  • ATP antagonists
  • CEP-1347
  • K252a dimer
  • PAKs
  • RAS
  • Signal therapy
  • Transformation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this