New FLT3 inhibitors could improve the treatment of acute myeloid leukaemia (AML), according to studies involving laboratory mice.
In about 30% of AML patients, their leukaemia carries an activating mutation in the FLT3 gene which makes the disease more aggressive. Existing FLT3 inhibitors such as midostaurin (Rydapt) and gilteritinib (marketed as Xospata in the US) are effective in treating FLT3-mutated AML. However, for some patients, their leukaemia relapses due to secondary mutations in FLT3.
Prof Herman Sintim of Purdue University, Indiana, USA, and his team developed new FLT3-inhibiting compounds based on alkynyl aminoisoquinoline and alkynyl napthyridine. In studies involving human AML cell lines in vitro and mouse models, the team demonstrated that these compounds are effective against both common FLT3 mutations and those mutations which confer drug resistance, including the F691L mutation.
Prof Sintim said: “These compounds have a great potential to be the next-generation acute myeloid leukaemia therapeutics for relapsed patients who no longer respond to first- or second-generation FLT3 inhibitors.
“In mouse studies, almost no leukaemia burden was visible after compound treatment for only a few weeks. Crucially this new class of FLT3 inhibitor also works against drug-resistant secondary mutations, such as the problematic F691L mutation.”
The researchers say that these new compounds have shown no signs of toxicity so far, do not appear to cause weight loss or other health problems, and could be taken orally.
The work was published on 25 January in the journal EBioMedicine.
Source: Naganna, N., Opoku-Temeng, C., Choi, E.Y., Larocque, E., Chang, E.T., Carter-Cooper, B.A., Wang, M., Torregrosa-Allen, S.E., Elzey, B.D., Lapidus, R.G., Sintim, H.O. (2019) “Amino alkynylisoquinoline and alkynylnaphthyridine compounds potently inhibit acute myeloid leukemia proliferation in mice”, EBioMedicine, available at doi: 10.1016/j.ebiom.2019.01.012
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