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  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.

Discovery, structure-guided design, and validation of WEHI-539, a novel, potent, and selective inhibitor of the pro-survival BCL-2 family member BCL-X<sub>L</sub>

245th National Meeting (2013)

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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

Discovery, structure-guided design, and validation of WEHI-539, a novel, potent, and selective inhibitor of the pro-survival BCL-2 family member BCL-X_L