Recently, a new type of targeting chaperon protein HSP70 inhibitor QL47 was discovered by a team led by Prof. LIU Qingsong from Hefei Institutes of Physical Science (HFIPS), Chinese Academy of Sciences, to treat FLT3-ITD-positive acute myeloid leukemia (AML).
Their findings have been published on Signal Transduction and Targeted Therapy.
"What we are seeking is a new therapeutic strategy which imperative for FLT3-ITD-positive AML," said HU Chen, leading author of the paper.
Approximately 25% of AMLs carry FLT3-ITD (internal tandem duplication) oncogenic mutations, and FLT3 kinase inhibitors have already achieved great success in the clinic for FLT3-ITD-positive AML. However, after prolonged treatment, drug-acquired resistance is observed in patients treated with FLT3 kinase inhibitor.
In this research, they found that compound QL47 had potent anti-proliferative activity against FLT3-ITD positive AML cell lines and induces FLT3-ITD protein degradation. Further study proved QL47 irreversibly bound to the heat shock protein HSP70 and inhibited its refolding activity, which in turn led to the degradation of FLT3-ITD and inhibited proliferation of the FLT3-ITD positive AML cells.
"It is inducible HSP70 instead of constitutive expressed HSC70 that is important for FLT3 protein stabilization and FLT3-ITD-positive cell viability,” Doctor HU explained their new finding.
The evaluation of QL47 in primary patient cells and in vivo tumor models showed that QL47 induced the degradation of FLT3-ITD protein and cell apoptosis in primary patient cells. In mice bone marrow engraftment model, QL47 significantly extends the animal survivals.
"Targeting the chaperone protein HSP70 could potentially provide a novel strategy for FLT3-ITD-positive AML treatment,” said HU.
Anti-tumor efficacy of QL47 in mouse tumor models (Image by HU Chen)
Hefei Institutes of Physical Science (http://english.hf.cas.cn/)