Poster Presentation RACI Biomolecular Division Conference 2013

Design and synthesis of a novel series of FLT3 inhibitors for treatment of acute myeloid leukaemia (#84)

Louisa J Phillipson 1 2 , Bill C Hawkins 1 2 , David H Segal 1 2 , Mark A Guthridge 3 , Andrew Wei 3 , Tracy L Nero 4 , Michael W Parker 4 , David CS Huang 1 2 , Christopher J Burns 1 2
  1. Chemical Biology, Walter & Eliza Hall Institute of Medical Research, Parkville, Vic, Australia
  2. Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
  3. Department of Clinical Haematology, Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
  4. ACRF Rational Drug Discovery Centre, St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
Acute myeloid leukaemia is the most prevalent leukaemia in adult patients. It is characterised by aggressive bone marrow malignancy giving rise to an overproduction of immature blast cells. Current chemotherapy regimes give rise to an overall 5 year survival rate of less than 40%. Given this poor prognosis there has been considerable interest in small molecule kinase inhibitors designed to target specific kinases implicated in AML. FMS-like tyrosine kinase 3 (FLT3) is one kinase that is dysregulated in AML, with activating mutations exhibited by ca. 25% of AML patients. These activating mutations are associated with a significantly poorer prognosis than is seen for AML patients with wild type FLT3. Clinical success of small molecule kinase inbibitors in AML has been limited through lack of efficacy and promiscuity of currently available inhibitors and the rapid emergence of resistance in treated patients. Here we present data on a novel series of compounds designed to inhibit FLT3 in conjunction with an improved profile.