Oral Presentation RACI Biomolecular Division Conference 2013

Examining AAL(S) as a New Lead for the Treatment of Leukaemia (#23)

Hamish D Toop 1 , Matt D Dun 2 , Nikki M Verrills 2 , Anthony S Don 3 , Jonathan C Morris 1
  1. School of Chemistry, The University of New South Wales, Sydney, NSW, Australia
  2. School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, NSW, Australia
  3. The Lowy Cancer Research Centre, Sydney, NSW, Australia

AAL(S), a synthetic analog of the endogenous lipid sphingosine, has recently been found have a broad range of biologically relevant activty.1,2   In particular, it has been found to be highly effective at inducing apoptosis in several leukaemia cell lines. Furthermore, it is able to eliminate cells which are resistant to current therapeutics without disruption to normal blood and bone marrow cells.3

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We have initiated a structure activity relationship study investigating changes to both the hydrophobic tail and aminoalcohol head group moiety of the AAL(S) scaffold. We have developed syntheses to access a range of analogs. These compounds have been tested for their activity against an acute lymphoblastic leukaemia cell line where preliminary data has revealed analogs with improved potency. Using this synthetic methodology a tagged analog has been prepared which is currently being used in affinity chromatography assays to identify AAL(S)'s protein binding partners. The outcome of this will help guide our efforts in drug design.

  1. Kim, H. J.; Qiao, Q.; Toop, H. D.; Morris, J. C.; Don, A. S. J. Lipid Res. 2012, 53, 1701.
  2. Collison, A.; Hatchwell, L.; Verrills, N.; Wark, P. A. B.; de Siqueira, A. P.; Tooze, M.; Carpenter, H.; Don, A. S.; Morris, J. C.; Zimmermann, N.; Bartlett, N. W.; Rothenberg, M. E.; Johnston, S. L.; Foster, P. S.; Mattes, J. Nat Med 2013, 19, 232.
  3. Jary, E., Bee, T., Walker, S. R., Chung, S., Seo, K., Morris, J. C., Don, A. S. Molecular Pharmacology. 2010, 78, 685.