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Challenges to the development of bryostatin-type anticancer drugs based on the activation mechanism of protein kinase Cδ.

Abstract
Protein kinase C (PKC) isozymes are widely recognized as targets for anticancer therapy, and recent investigations demonstrated that PKC activators are potential therapeutic candidates for Alzheimer's disease and acquired immune deficiency syndrome. However, concerns exist about their therapeutic uses because most PKC activators are potent tumor promoters. Bryostatin 1 (bryo-1) is a unique PKC activator with little tumor-promoting activities. Bryo-1 is currently undergoing clinical trials for the treatment of cancer. However, its limited availability from natural sources and difficulty in the synthesis hamper further studies on its mode of action and structural optimization. Although excellent practical methods for synthesizing several bryo-1-related compounds have been developed, the identification of synthetically more accessible compounds with bryo-1-like activity also provides a promising way to circumvent the problem of supply. The authors focused on the bryo-1's unique mechanism of activating PKCδ that plays a tumor suppressor role, and found that a simple and less lipophilic analogue (aplog-1) of the tumor-promoting aplysiatoxin showed PKCδ-activating behavior similar to bryo-1. Aplog-1 was easily synthesized in only 22 steps using standard reactions. Moreover, its tumor-promoting activity in vitro was very weak, and its cell growth-inhibitory activities were comparable to those of bryo-1. These data suggest that aplog-1 could become another therapeutic lead for cancer.
AuthorsKazuhiro Irie, Ryo C Yanagita, Yu Nakagawa
JournalMedicinal research reviews (Med Res Rev) Vol. 32 Issue 3 Pg. 518-35 (May 2012) ISSN: 1098-1128 [Electronic] United States
PMID22539107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
Copyright© 2010 Wiley Periodicals, Inc.
Chemical References
  • Antineoplastic Agents
  • Bryostatins
  • bryostatin 1
  • Protein Kinase C-delta
Topics
  • Antineoplastic Agents (chemical synthesis, pharmacology)
  • Bryostatins (pharmacology)
  • Enzyme Activation (drug effects)
  • Humans
  • Protein Kinase C-delta (metabolism)

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