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


CONCLUSIONS
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.
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Australia.
Thao V
TV
Nheu
Hong
H
He
Yumiko
Y
Hirokawa
Kazuhiko
K
Tamaki
Lore
L
Florin
M Lienhard
ML
Schmitz
Ikuko
I
Suzuki-Takahashi
Robert N
RN
Jorissen
Antony W
AW
Burgess
Susumu
S
Nishimura
John
J
Wood
Hiroshi
H
Maruta
D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D000818:Animals; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011905:Genes, ras; D026121:Indole Alkaloids; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000737:chemistry; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D000255:Adenosine Triphosphate; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D007211:Indoles; D020930:MAP Kinase Kinase Kinases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C106592:3,9-bis((ethylthio)methyl)-K-252a; C049985:staurosporine aglycone