Structure-guided design of a selective BCL-XL inhibitor Academic Article uri icon

abstract

  • The prosurvival BCL-2 family protein BCL-X(L) is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-X(L) will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-X(L)-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-X(L) and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-X(L) and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-X(L) from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-X(L) for their sustained growth.

authors

  • Lessene, Guillaume
  • Czabotar, Peter E
  • Sleebs, Brad E
  • Zobel, Kerry
  • Lowes, Kym N
  • Adams, Jerry M
  • Baell, Jonathan B
  • Colman, Peter M
  • Deshayes, Kurt
  • Fairbrother, Wayne J
  • Flygare, John A
  • Gibbons, Paul
  • Kersten, Wilhelmus JA
  • Kulasegaram, Sanji
  • Moss, Rebecca M
  • Parisot, John P
  • Smith, Brian J
  • Street, Ian P
  • Yang, Hong
  • Huang, David CS
  • Watson, Keith G

publication date

  • June 2013