K252a, KT5720, KT5926, and U98017 support paclitaxel (taxol)-dependent cells and synergize with paclitaxel.
We have used paclitaxel-dependent Tax 2-4 cells to screen for compounds that have paclitaxel-like functional activity. The indolocarbazole serine/threonine kinase inhibitor K252a and analogues such as KT5926, KT5720, and K252b partially support the growth of the paclitaxel-dependent cells in the absence of paclitaxel. A novel kinase inhibitor of similar structure, U98017, supports the growth of the dependent cells to 48% of that seen with paclitaxel. Used in combination with paclitaxel, these compounds reduce the amount of paclitaxel required for maximum growth of the dependent cells. Isobologram analysis demonstrates that these compounds also act synergistically with paclitaxel to promote toxicity in wild-type Chinese hamster ovary cells. These selected indolocarbazoles may act at sites distinct from that of paclitaxel and may specifically inhibit kinases that contribute to the destabilization of microtubules. Other indolocarbazoles such as staurosporine and rebeccamycin do not support paclitaxel-dependent cell growth. Structurally unrelated serine/threonine kinase inhibitors such as H-9 and H-7 or tyrosine kinase inhibitors such as lavendustin do not support the growth of these cells. These results define a screen for functional paclitaxel analogues and suggest that it may be useful to investigate the possible synergy of selected indolocarbazoles and paclitaxel in vivo.
Upjohn Company, Kalamazoo, Michigan 49007.
I
I
Abraham
C L
CL
Wolf
K E
KE
Sampson
A L
AL
Laborde
J A
JA
Shelly
P A
PA
Aristoff
H I
HI
Skulnick
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells / Q000187:drug effects* / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D004357:Drug Synergism; D026121:Indole Alkaloids; D007211:Indoles / Q000494:pharmacology*; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors*; D017239:Paclitaxel / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D019311:Staurosporine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D002227:Carbazoles; D026121:Indole Alkaloids; D007211:Indoles; D011758:Pyrroles; C063769:KT 5926; C057416:KT 5720; C049985:staurosporine aglycone; D009219:Myosin-Light-Chain Kinase; D019311:Staurosporine; D017239:Paclitaxel