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 Jorissen, Antony W. Burgess, Susumu Nishimura, John Wood, Hiroshi Maruta

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

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.

LanguageEnglish
Pages328-336
Number of pages9
JournalCancer Journal
Volume8
Issue number4
DOIs
Publication statusPublished - 1 Aug 2002

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nheu, Thao V. ; He, Hong ; Hirokawa, Yumiko ; Tamaki, Kazuhiko ; Florin, Lore ; Schmitz, M. Lienhard ; Suzuki-Takahashi, Ikuko ; Jorissen, Robert ; Burgess, Antony W. ; Nishimura, Susumu ; Wood, John ; Maruta, Hiroshi. / The K252a derivatives, inhibitors for the PAK/MLK kinase family, selectively block the growth of RAS transformants. In: Cancer Journal. 2002 ; Vol. 8, No. 4. pp. 328-336.
@article{e2ca9d344773444289be6a0a0cbace89,
title = "The K252a derivatives, inhibitors for the PAK/MLK kinase family, selectively block the growth of RAS transformants",
abstract = "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.",
keywords = "ATP antagonists, CEP-1347, K252a dimer, PAKs, RAS, Signal therapy, Transformation",
author = "Nheu, {Thao V.} and Hong He and Yumiko Hirokawa and Kazuhiko Tamaki and Lore Florin and Schmitz, {M. Lienhard} and Ikuko Suzuki-Takahashi and Robert Jorissen and Burgess, {Antony W.} and Susumu Nishimura and John Wood and Hiroshi Maruta",
year = "2002",
month = "8",
day = "1",
doi = "10.1097/00130404-200207000-00009",
language = "English",
volume = "8",
pages = "328--336",
journal = "Cancer Journal",
issn = "1528-9117",
number = "4",

}

Nheu, TV, He, H, Hirokawa, Y, Tamaki, K, Florin, L, Schmitz, ML, Suzuki-Takahashi, I, Jorissen, R, Burgess, AW, Nishimura, S, Wood, J & Maruta, H 2002, 'The K252a derivatives, inhibitors for the PAK/MLK kinase family, selectively block the growth of RAS transformants', Cancer Journal, vol. 8, no. 4, pp. 328-336. https://doi.org/10.1097/00130404-200207000-00009

The K252a derivatives, inhibitors for the PAK/MLK kinase family, selectively block the growth of RAS transformants. / Nheu, Thao V.; He, Hong; Hirokawa, Yumiko; Tamaki, Kazuhiko; Florin, Lore; Schmitz, M. Lienhard; Suzuki-Takahashi, Ikuko; Jorissen, Robert; Burgess, Antony W.; Nishimura, Susumu; Wood, John; Maruta, Hiroshi.

In: Cancer Journal, Vol. 8, No. 4, 01.08.2002, p. 328-336.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The K252a derivatives, inhibitors for the PAK/MLK kinase family, selectively block the growth of RAS transformants

AU - Nheu, Thao V.

AU - He, Hong

AU - Hirokawa, Yumiko

AU - Tamaki, Kazuhiko

AU - Florin, Lore

AU - Schmitz, M. Lienhard

AU - Suzuki-Takahashi, Ikuko

AU - Jorissen, Robert

AU - Burgess, Antony W.

AU - Nishimura, Susumu

AU - Wood, John

AU - Maruta, Hiroshi

PY - 2002/8/1

Y1 - 2002/8/1

N2 - 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.

AB - 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.

KW - ATP antagonists

KW - CEP-1347

KW - K252a dimer

KW - PAKs

KW - RAS

KW - Signal therapy

KW - Transformation

UR - http://www.scopus.com/inward/record.url?scp=0036635758&partnerID=8YFLogxK

U2 - 10.1097/00130404-200207000-00009

DO - 10.1097/00130404-200207000-00009

M3 - Article

VL - 8

SP - 328

EP - 336

JO - Cancer Journal

T2 - Cancer Journal

JF - Cancer Journal

SN - 1528-9117

IS - 4

ER -