Protein kinase C inhibitors as novel anticancer drugs.
The role of PKC isoforms in signal transduction pathways involved in regulation of the cell cycle, apoptosis, angiogenesis, differentiation, invasiveness, senescence and drug efflux are reviewed, along with the clinical results on the current crop of PKC inhibitors, including midostaurin (PKC-412, CGP 41251, N -benzoylstaurosporine), UCN-01 (7-hydroxystaurosporine), bryostatin 1, perifosine, ilmofosine, Ro 31-8220, Ro 32-0432, GO 6976, ISIS-3521 (CGP 64128A) and the macrocyclic bis (indolyl) maleimides (LY-333531, LY-379196, LY-317615). An appreciation of the complex, often contradictory roles of PKC isoforms in signal transduction pathways involved in cancer is important for interpreting the clinical results observed with PKC inhibitors of varying selectivity. An antisense oligonucleotide, ISIS-3521 and two orally available small molecule inhibitors, LY 333531 and midostaurin, have now advanced to latter stage development for cancer and/or other indications. These compounds have varying levels of selectivity for the PKC isoforms and for the kinase and initial safety and early clinical efficacy have been encouraging. At this stage, the potential of PKC inhibition for the treatment of cancer has not been fully realised. The concurrent inhibition of multiple PKC isoforms may yet provide an improved clinical outcome in treating cancers in view of the complex interrelated roles of the PKC isoforms.
Goekjian
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PG
Laboratoire Chimie Organique II/UMR 5622, Universite Claude Bernard Lyon 1; Bat. 308-CPE, 3 Rue Victor Grignard, 69622 Villeurbanne Cedex, France. goekjian@univ-lyon1.fr
Jirousek
M R
MR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011493:Protein Kinase C