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Discovery of a highly potent FLT3 kinase inhibitor for FLT3-ITD-positive AML

Leukemia volume 30, pages 2112–2116 (2016)Cite this article

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Acute myeloid leukemia (AML) is one of the most common leukemias in adults and if not treated is rapidly fatal.1 FLT3 kinase plays a critical role in the differentiation and survival of hematopoietic stem cells in bone marrow.2 The internal tandem duplication of FLT3 kinase (FLT3-ITD) as a driving oncogenic mutation has been found in ~30% of the AML patients and has been actively pursued as a drug discovery target for AML.3 A number of small-molecule inhibitors of FLT3 kinase exist that are undergoing clinical investigation such as crenolanib,4 AC220 (quizartinib)5 and PKC412 (midostaurin).6, 7 Recently PKC412 has received Food and Drug Administration (FDA)’s break through therapy designation for the FLT3-ITD+ 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.8 Recently, we discovered that the BTK kinase inhibitor, ibrutinib (PCI-32765), displays a sub-micromolar growth inhibition of 50% (GI50) against FLT3-ITD-positive AML cancer cell lines, such as MOLM13, MOLM14 and MV4-11,9 however, exhibits no apparent activity against c-KIT. An effort to improve the efficacy of ibrutinib led to the development of 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.

In summary, we have discovered a highly potent FLT3 kinase inhibitor, CHMFL-FLT3-165, which exhibits strong biochemical inhibition against FLT3 wt/ITD kinases, potent anti-proliferation effects against FLT3-ITD-positive leukemia cell lines and patient primary cells, as well as significant in vivo tumor suppression. Compared with the FLT3 inhibitors currently received FDA approval (PKC412) and inhibitor in advanced-stage clinical development (such as AC220), compound 165 may be associated with less adverse effects, such as myelosuppression, in that it exhibited over 20-fold selectivity toward FLT3 versus c-KIT kinase. Potent suppression of the drug-resistant FLT3-ITD mutations (FLT3-ITD-D835Y and F691L) combined with tyrosine kinase domain point mutants (D835Y/E/H) is also potentially clinically advantageous. Compound 165 displays GI50s of less than 100 nm against these compound mutations in the TEL-transfused BaF3 cells, which is comparable potency to that exhibited by crenolanib.4 Although our studies show that compound 165 is selective for FLT3 as an oncogenic target, it should be noted that contribution of other drug targets of compound 165, such as Her2 and PDGFRβ, to the observed anti-leukemia effects cannot be ruled out. Taken together, we believe CHMFL-FLT3-165 might be a valuable potential novel therapeutic agent for FLT3-ITD-positive AML. CHMFL-FLT3-165 is currently undergoing extensive preclinical safety evaluation.

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Acknowledgements

JL, QL and WW are supported by the grant of ‘Cross-disciplinary Collaborative Teams Program for Science, Technology and Innovation (2014−2016)’ from Chinese Academy of Sciences. ZZ is supported by Anhui Province Natural Science Foundation Annual Key Program (grant number: 1301023011). We thank China ‘Thousand Talents Program’ support for QL and ‘Hundred Talents Program’ of The Chinese Academy of Sciences support for JL and WW. ZZ is supported by Key Projects of Provincial Natural Science Research in Colleges and Universities of Anhui Province (grant number: KJ2014Z017). JL is also supported by the National Program for Support of Top-notch Young Professionals. QL is also supported by the CAS/SAFEA International Partnership Program for Creative Research Teams.

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Author notes

  1. H Wu, A Wang, Z Qi, X Li and C Chen: These authors contributed equally to this work.

Authors and Affiliations

  1. High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, China

    H Wu, A Wang, Z Qi, X Li, C Chen, K Yu, F Zou, C Hu, W Wang, Z Zhao, J Wu, J Liu, X Liu, L Wang, W Wang, J Liu & Q Liu

  2. University of Science and Technology of China, Hefei, China

    H Wu, A Wang, K Yu, C Hu, J Wu, J Liu, X Liu & Q Liu

  3. CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, China

    Z Qi, X Li, C Chen, F Zou, W Wang, Z Zhao, L Wang, W Wang, S Zhang, J Liu & Q Liu

  4. Hefei Cosource Medicine Technology Co. LTD., Hefei, China

    S Zhang

  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    R M Stone, I A Galinsky, J D Griffin, D Weinstock, A Christodoulou & E L Weisberg

  6. Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, China

    H Wang, Y Shen & Z Zhai

  7. Hematology Research Center, Anhui Medical University, Hefei, China

    H Wang, Y Shen & Z Zhai

  8. Hefei Science Center, Chinese Academy of Sciences, Hefei, China

    Q Liu

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Corresponding authors

Correspondence to Z Zhai, E L Weisberg, J Liu or Q Liu.

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Dr. Shanchun Zhang is shareholder of Hefei Cosource Medicine Technology Co. LTD.

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Wu, H., Wang, A., Qi, Z. et al. Discovery of a highly potent FLT3 kinase inhibitor for FLT3-ITD-positive AML. Leukemia 30, 2112–2116 (2016). https://doi.org/10.1038/leu.2016.151

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