Anti-leukemia effects of CHMFL-FLT3-165 in an MV4-11-inoculated mouse model.  Photo by WaNg aoli aNd PiNg Qizi

A recent study, jointly conducted by Prof. Liu Qingsong's group and Liu Jing's group at the High Magnetic Field Laboratory, Hefei Institutes of Physical Sciences, Chinese Academy of Sciences (CHMFL), developed a highly potent FLT3 kinase inhibitor for FLT3-ITD-positive Acute Myeloid Leukemia (AML).

AML is one of the most common leukemias in adults and is rapidly fatal if not treated. FLT3 kinase plays a critical role in the differentiation and survival of hematopoietic stem cells in bone marrow. The internal tandem duplication of FLT3 kinase (FLT3-ITD) as a driving oncogenic mutation has not only been found in approximately 30 percent of AML patients but has also been actively pursued as a drug discovery target for AML.

There exist a number of small molecule inhibitors of FLT3 kinase that are undergoing clinical investigation, such as crenolanib, AC220 (quizartinib), and PKC412 (midostaurin). PKC412 has received FDA’s breakthrough therapy designation for the FLT3-ITD-positive AML. The preclinical studies demonstrated that myelosuppression toxicity of PKC412 and AC220 might be due to off-target effects, such as inhibition of c-KIT.

Anti-proliferation effects of CHMFL-FLT3-165 on FLT3-ITD-positive AML patient primary cells. Photo by WaNg aoli aNd PiNg Qizi

Recently the research team discovered that the BTK kinase inhibitor, ibrutinib (PCI-32765), displays a sub-micromolar GI50 against FLT3-ITD-positive AML cancer cell lines; however it exhibits no apparent activity against c-KIT.

An effort to improve the efficacy of ibrutinib led to the development of the novel and highly potent FLT3 kinase inhibitor, CHMFL-FLT3-165, which displays high selectivity toward BTK and c-KIT kinases, and exhibits impressive inhibitory efficacy against FLT3-ITD-positive AML cancer cell lines and mutant FLT3- expressing primary patient cells, and reduces leukemia growth in preclinical in vivo xenograft and engraftment models.

This work was published online as Discovery of a Highly Potent FLT3 Kinase Inhibitor for FLT3-ITD Positive AML in the journal Leukemia.

The research group has already applied for Chinese patent and international patent protection.

Contact:

Liu Qingsong

High Magnetic Field Laboratory, Hebei Institutes of Physical Science, Chinese Academy of Sciences (http://english.hmfl.cas.cn/)

350 Shushanhu Road, Hefei, Anhui, 230031 P. R. China

Email: qsliu97@hmfl.ac.cn