Dienone Compounds: Targets and Pharmacological Responses

Martina Bazzaro, Stig Linder

Research output: Contribution to journalReview articlepeer-review

Abstract

The biological responses to dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been studied extensively. Despite their expected general thiol reactivity, these compounds display considerable degrees of tumor cell selectivity. Here we review in vitro and preclinical studies of dienone compounds including b-AP15, VLX1570, RA-9, RA-190, EF24, HO-3867, and MCB-613. A common property of these compounds is their targeting of the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. Gene expression profiling experiments have shown induction of responses characteristic of UPS inhibition, and experiments using cellular reporter proteins have shown that proteasome inhibition is associated with cell death. Other mechanisms of action such as reactivation of mutant p53, stimulation of steroid receptor coactivators, and induction of protein cross-linking have also been described. Although unsuitable as biological probes due to widespread reactivity, dienone compounds are cytotoxic to apoptosis-resistant tumor cells and show activity in animal tumor models.

Original languageEnglish (US)
Pages (from-to)15075-15093
Number of pages19
JournalJournal of medicinal chemistry
Volume63
Issue number24
DOIs
StatePublished - Dec 24 2020

Bibliographical note

Funding Information:
This work was supported by Department of Defense Ovarian Cancer Research Program Grant OC160377, the Minnesota Ovarian Cancer Alliance, the Randy Shaver Cancer Research Funds and the NIH grant NIGMS R01-GM130800 to Martina Bazzaro.

Publisher Copyright:
© 2020 American Chemical Society. All rights reserved.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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