Enzyme structure raises hope of new drugs
crystal structure of Flt-3, a member of the receptor tyrosine
kinase family that is implicated in the development and progression
of leukaemia, paving the way for the development of new drugs to
treat the disease.
The study provides direct insight into the mechanism by which mutated forms of the Flt-3 receptor can activate themselves and trigger uncontrolled proliferation of immature blood cells, a common feature of several types of leukaemia.
Mutations in Flt-3 are most common in acute myeloid leukemia (AML), and they are associated with a poor prognosis of disease. Exploring the mechanism by which these Flt-3 mutations cause uncontrolled proliferation through their overactive state may provide insights for the design and development of new small molecule drugs.
Kinases catalyse phosphorylation or the transfer of a phosphate group from ATP - the primary source of energy for metabolic processes in the cell. They can be associated with receptors on the cell surface, and when a ligand binds to the receptor, kick off the chain of events that transfers that signal into the cell.
Based on an analysis of the crystal structure, Vertex scientists have put forward the hypothesis that certain genetic mutations cause the portion of the enzyme that abuts the cell membrane to change its structure in such a way that the receptor phosphorylates itself. Effectively this means that the signal from the receptor becomes permanently switched on, and the cell begins to proliferate uncontrollably.
The research is published in the 30 January issue of the journal Molecular Cell.
"Several research groups have already demonstrated that a mutated form of Flt-3 can activate itself, and our analysis of the crystal structure suggests how this can occur," commented James Griffith, a Vertex researcher and lead author of the study.
Also because there is so much similarity between the receptor tyrosine kinase family, and given that they are over-activated in many tumour types, it could be that that the mechanism Vertex has identified could have far-reaching implications for the development of small molecule cancer therapies.
Flt-3 is primarily expressed in immature haematopoietic cells, which are responsible for generating blood cells, and is essential for the normal function of stem cells and the immune system.
Flt-3 is expressed in high levels in a wide range of leukaemias, including 70 to 100 per cent of AML, acute lymphoblastic leukaemia (ALL) and chronic myelogenous leukaemia (CML). Furthermore, activating Flt-3 mutations are present in up to 40 per cent of AML patients.
According to the American Cancer Society, in 2003, 30,600 patients were diagnosed in the US with leukaemia, more than a third of whom have AML. The ACS estimates that AML resulted in 7,800 deaths in the US in 2003.
