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Ref Type Journal Article
PMID (12184411)
Authors Nheu TV, He H, Hirokawa Y, Tamaki K, Florin L, Schmitz ML, Suzuki-Takahashi I, Jorissen RN, Burgess AW, Nishimura S, Wood J, Maruta H
Title The K252a derivatives, inhibitors for the PAK/MLK kinase family selectively block the growth of RAS transformants.
Journal Vol Issue Date Pages Journal Short Title
Cancer journal (Sudbury, Mass.) 8 4 2002 Jul-Aug 328-36 Cancer J
URL
Abstract Text 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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CEP1347 CEP1347 1 0
KTD606 KTD606 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CEP1347 CEP-1347|CEP 1347 CEP1347 inhibits PAK and MLK family kinases, which potentially induces differentiation and inhibits cancer stem cell self-renewal and tumor growth (PMID: 29212273, PMID: 12184411).
KTD606 KTD-606|KTD 606|KT-D606|KT-D606|KT D606 PAK1 Inhibitor 11 KTD606 is an ATP-competitive inhibitor of PAK1 and mixed-lineage kinases (MLKs), potentially inhibiting proliferation of transformed cells (PMID: 12184411).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References