Targeting BFL-1 for the treatment of cancer

Targeting BFL-1 for the treatment of cancer

Partnering opportunity in cancer: 

Targeting BFL-1 for the treatment of cancer

 

Team

Professor Andreas Strasser, Associate Professor Guillaume Lessene, Dr Marco Herold, Dr Douglas Fairlie, Dr Erinna Lee

Background

Melanoma is amongst the top five most common cancers in Australia and the US. Although surgery is effective for treating early stage melanoma, metastatic melanoma remains one of the most difficult cancers to cure.

Recent breakthroughs in the understanding of melanoma progression have led to the development of targeted therapies, for example mutant BRAF inhibitors. However, these only have a minor impact on patient prognosis and provide no likelihood of a curative outcome, with all patients eventually relapsing.

Emerging evidence identifies the pro-survival Bcl-2 family member, BFL-1, as a critical factor for melanoma cells. BFL-1 is expressed at unusually high levels, which has been reported to serve as a key mechanism of resistance to currently available therapies, including mutant BRAF inhibitors.

While a number of compounds have been developed that target its homologues, compounds that target BFL-1 have proved elusive.

The technology

Our researchers have used high throughput screening to identify new BFL-1 inhibitors.

We are currently confirming hits from the primary screen. We have also conducted fragment-based screening and are testing a number of the primary hits. From these studies we have developed a novel BFL-1-specific tool compound, and have demonstrated that inhibition of BFL-1 using this compound is sufficient to kill melanoma cells.

Capabilities and resources to enable high quality hit-to-lead and lead optimisation studies are at available at both the Walter and Eliza Hall and Olivia Newton-John Cancer Research Institutes, including:

  1. The ability to produce purified BFL-1 in quantities and purity suitable for hit validation and structural studies
  2. A tool peptide-based compound selective for BFL-1, which has been employed to identify BFL-1-dependent cancer cell lines for hit validation
  3. Genetically engineered cell lines/animal models

Applications

In addition to melanoma, B cell lymphoma and T cell lymphoma exhibit abnormally elevated levels of BFL-1 and may also respond to treatment with BFL-1 inhibitors.

Intellectual property

Compound structures have not been publicly disclosed. An opportunity exists to generate novel composition of matter intellectual property.

Opportunity for partnership

We seek a partner to invest in the development of novel small molecule compounds specifically targeting BFL-1. The ultimate goal is to continue developing a small molecule clinical candidate as well as back-up compounds with appropriate potency, safety and pharmacokinetic profiles.

Our scientists are world leaders in apoptosis, and have significant expertise and capacity to conduct medicinal chemistry.

Key publications

  • Haq R. et al. BCL2A1 is a lineage-specific anti-apoptotic melanoma oncogene that confers resistance to BRAF inhibition. Proc Natl Acad Sci U S A. 2013 Mar 12;110(11) 4321-6 PMID: 23447565
  • Yecies D. et al. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood. 2010 Apr 22;115(16):3304-13. PMID: 20197552
  • Vogler M. et al. 2009. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood. 2009 Apr 30;113(18):4403-13. PMID: 19008458

Contact

Dr David Segal, Technology Development Associate

Phone: +61 3 9345 2418  Email: segal@wehi.edu.au

 

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