BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines

Delphine Merino, Gemma L. Kelly, Guillaume Lessene, Andrew H. Wei, Andrew W. Roberts, Andreas Strasser

Research output: Contribution to journalReview ArticleResearchpeer-review

85 Citations (Scopus)

Abstract

Defects in apoptotic cell death can promote cancer and impair responses of malignant cells to anti-cancer therapy. Pro-survival BCL-2 proteins prevent apoptosis by keeping the cell death effectors, BAX and BAK, in check. The BH3-only proteins initiate apoptosis by neutralizing the pro-survival BCL-2 proteins. Structural analysis and medicinal chemistry led to the development of small-molecule drugs that mimic the function of the BH3-only proteins to kill cancer cells. The BCL-2 inhibitor venetoclax has been approved for treatment of refractory chronic lymphocytic leukemia and this drug and inhibitors of pro-survival MCL-1 and BCL-XL are being tested in diverse malignancies. Defects in apoptotic cell death can promote cancer and impair responses of malignant cells to anti-cancer therapy. Pro-survival BCL-2 proteins prevent apoptosis by keeping the cell death effectors, BAX and BAK, in check. The BH3-only proteins initiate apoptosis by neutralizing the pro-survival BCL-2 proteins. Structural analysis and medicinal chemistry led to the development of small-molecule drugs that mimic the function of the BH3-only proteins to kill cancer cells. The BCL-2 inhibitor venetoclax has been approved for treatment of refractory chronic lymphocytic leukemia and this drug and inhibitors of pro-survival MCL-1 and BCL-XL are being tested in diverse malignancies.

Original languageEnglish
Pages (from-to)879-891
Number of pages13
JournalCancer Cell
Volume34
Issue number6
DOIs
Publication statusPublished - 10 Dec 2018

Keywords

  • apoptosis
  • BCL-2
  • BH3-mimetic drugs
  • BH3-only proteins
  • cancer
  • MCL-1

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