Oral Presentation RACI Biomolecular Division Conference 2013

Discovery, structure-guided design and validation of WEHI-539, a novel, potent and selective inhibitor of the pro-survival BCL-2 family member BCL-XL (#3)

Guillaume Lessene 1 , Peter E Czabotar 2 , Brad E Sleebs 2 , Kerry Zobel 3 , Kym L Lowes 2 , Jerry M Adams 2 , Jonathan B Baell 2 , Yu Chen , Peter M Colman 2 , Kurt Deshayes 3 , Wayne J Fairbrother 3 , John A Flygare 3 , Sha Jin 4 , Paul Gibbons 3 , Wilhelmus JA Kersten 2 , Sanji Kulasegaram 2 , Joel Leverson 4 , Rebecca M Moss 2 , John P Parisot 2 , Brian J Smith 2 , Ian P Street 2 , Hong Yang 2 , David CS Huang 2 , Keith G Watson 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  3. Genentech Inc., South San Francisco, California, USA
  4. Abbvie, North Chicago, Illinois, USA

Pro-survival BCL‑2-family proteins are often over-expressed in tumours and essential for their sustained expansion.1 Moreover, the pro-survival BCL-2 family member BCL‑XL renders malignant tumour cells resistant to diverse anti-cancer therapeutics.2  Hence, enhancing apoptotic responses by inhibiting BCL‑XL is likely to have widespread utility in cancer treatment and, compared to inhibiting multiple pro-survival BCL-2 family members, a BCL‑XL-selective inhibitor would be expected to minimize the toxicity to normal tissues.

The BCL-2 family driven apoptosis occurs through a protein-protein interaction cascade between pro-survival and pro-apoptotic members of the family.3  Targeting these proteins — deemed “undruggable” by many pharmaceutical companies — with small molecules has historically been a considerable challenge.

Here, we describe the discovery (by high throughput screen) of a novel series of small molecules targeting BCL‑XL and their structure-guided development. The optimized compound, WEHI-539, has high affinity (sub-nM) and unprecedented selectivity for BCL‑XL. We show that WEHI-539 potently kills cells by selectively antagonizing the pro-survival activity of BCL‑XL.4   WEHI-539 will be an invaluable in vitro tool for distinguishing the roles of BCL-XL from those of its pro-survival relatives, both in normal cells and crucially in malignant tumor cells, many of which may prove to rely upon BCL‑XL for their sustained growth.

  1. Kelly, P.N. & Strasser, A. The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. 18, 1414-24 (2011)
  2. Amundson, S.A. et al. An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res. 60, 6101-10 (2000)
  3. Lessene, G., Czabotar, P.E. & Colman, P.M. BCL-2 family antagonists for cancer therapy. Nat. Rev. Drug Discov. 7, 989-1000 (2008)
  4. Lessene, G. et al. Discovery, structure-guided design and validation of a novel, potent and selective inhibitor of the pro-survival BCL-2 family member BCL-XL. Submitted