Enzymatic rationale and preclinical support for a potent protein kinase C beta inhibitor in cancer therapy.
The macrocyclic bisindolylmaleimide, LY333531, selectively inhibits protein kinase C beta 1 and beta 2 isoforms with an approximate IC50 of 5 nanomolar. The efficacy of LY333531 administered alone and in combination with cytotoxic cancer therapies in models of non-small cell lung carcinoma and brain tumors was determined in vivo. In the Lewis lung carcinoma, administration of LY333531 enhanced the activity of paclitaxel and fractionated radiation and, to a lesser degree, carboplatin and gemcitabine. In the human T98G glioblastoma multiforme xenograft, the addition of LY333531 to treatment with carmustine (BCNU) resulted in enhanced tumor response in a nodule grown subcutaneously and increased life-span in animals bearing an intracranial tumor from 37 days in the control animals to 64 days in the BCNU treated animals, and to 104 days in the LY333531 plus BCNU treated animals with 4 out of 5 animals being long-term survivors.
Teicher
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BA
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Alvarez
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Mendelsohn
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LG
Ara
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G
Menon
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Ways
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DK
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008301:Maleimides / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology* / Q000532:radiotherapy; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta