Poster Presentation 25th Lorne Cancer Conference 2013

Discovery, Structure-Guided Design and Biological Validation of the First Potent and Selective Inhibitor of the Pro-Survival BCL-2 Family Member BCL-XL (#245)

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

Pro-survival BCL‑2-family proteins are often over-expressed in tumours and essential for their sustained expansion. Moreover, the pro-survival BCL-2 family member BCL‑XL renders malignant tumour cells resistant to diverse anti-cancer therapeutics. 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. Here, we describe the discovery by a high throughput screen of a novel series of small molecules targeting BCL‑XL and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539, has high affinity (sub-nM) and selectivity for BCL‑XL and potently kills cells by selectively antagonizing the pro-survival activity of BCL‑XL. WEHI-539 is an invaluable 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.