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ACUTE MYELOID LEUKEMIA

Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia

Leukemia volume 37, pages 539–549 (2023)Cite this article

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Abstract

FLT3 inhibitors (FLT3i) are widely used for the treatment of acute myeloid leukemia (AML), but adaptive and acquired resistance remains a primary challenge. Inhibitors simultaneously blocking adaptive and acquired resistance are highly demanded. Here, we observed the potential of CHK1 inhibitors to synergistically improve the therapeutic effect of FLT3i in FLT3-mutated AML cells. Notably, the combination overcame adaptive resistance. The simultaneous targeting of FLT3 and CHK1 kinases may overcome acquired and adaptive resistance. A dual FLT3/CHK1 inhibitor 30 with a good oral PK profile was identified. Mechanistic studies indicated that 30 inhibited FLT3 and CHK1, downregulated the c-Myc pathway and further activated the p53 pathway. Functional studies showed that 30 was more selective against cells with various FLT3 mutants, overcame adaptive resistance in vitro, and effectively inhibited resistant FLT3-ITD AML in vivo. Moreover, 30 showed favorable druggability without significant blood toxicity or myelosuppression and exhibited a good oral PK profile with a T1/2 over 12 h in beagles. These findings support the targeting of FLT3 and CHK1 as a novel strategy for overcoming adaptive and acquired resistance to FLT3i therapy in AML and suggest 30 as a potential clinical candidate.

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Fig. 1: CHK1 inhibitors harbor sensitivity to FLT3-mutated cells and improve the efficacy of FLT3 inhibitor therapy.
Fig. 2: Identification of potential dual FLT3/CHK1 inhibitors for AML with FLT3 mutation.
Fig. 3: Compound 30 blocks FLT3 and CHK1 signaling and potently inhibits acquired and adaptive resistance in FLT3-mutated AML cells.
Fig. 4: Compound 30 blocks FLT3-ITD AML tumor growth and allows prolonged survival in vivo.
Fig. 5: Druggability profile of compound 30.

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Acknowledgements

We thank all the patients whose samples used in the study and their families. We thank Jianyang Pan (Research and Service Center, College of Pharmaceutical Sciences, Zhejiang University) for performing NMR spectrometry for structure elucidation. We also thank Huazhou Ying (College of Pharmaceutical Sciences, Zhejiang University) for performing mass spectrometry for structure elucidation.

Funding

This work was supported by grants from the Guangdong High-level new R&D Institute (2019B090904008) and the Guangdong High-level Innovative Research Institute (2021B0909050003), the key project of Zhejiang Provincial Natural Science Foundation of China (LZ21H300001), the National Natural Science Foundation of China (81821005, 82204179), the Science and Technology Commission of Shanghai Municipality (18431907100, 19430750100).

Author information

Author notes

  1. These authors contributed equally: Kailong Jiang, Xuemei Li, Chang Wang, Xiaobei Hu.

Authors and Affiliations

  1. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangdong, 528400, China

    Kailong Jiang, Xiaobei Hu, Jia Li & Yubo Zhou

  2. ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China

    Xuemei Li, Lexian Tong, Tingting Jin & Tao Liu

  3. National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Chang Wang, Xiaobei Hu, Peipei Wang, Yutong Tu, Hanlin Wang, Yubing Han, Jia Li & Yubo Zhou

  4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China

    Peipei Wang, Jia Li & Yubo Zhou

  5. School of Materials Science and Engineering, Zhejiang University, Hangzhou, Zhejiang, 310027, China

    Lexian Tong

  6. Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, Zhejiang, 310018, China

    Lexian Tong

  7. University of Chinese Academy of Sciences, Beijing, 100049, China

    Yutong Tu, Yubing Han, Jia Li & Yubo Zhou

  8. School of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, 550025, China

    Beijing Chen & Jia Li

  9. Translational Medicine Research Center, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China

    Tingting Jin

  10. Changhai Hospital, Naval Medical University, Shanghai, 200433, China

    Tao Wang & Jianmin Yang

  11. School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, 563006, China

    Renzhao Gui & Jia Li

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  1. Kailong Jiang
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  2. Xuemei Li
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  3. Chang Wang
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Contributions

KLJ, XML, CW, XBH, TL, YBZ and JL conceived and designed the study. KLJ, CW and YTT performed in vitro cellular experiments, analyzed the data and interpreted the results. PPW performed in vitro enzymatic assays, analyzed the data and interpreted the results. XBH, BJC and RZG performed in vivo experiments, analyzed the data and interpreted the results. XML, LXT, TTJ and TL designed and synthesized the compounds, analyzed the data and interpreted the results. HLW and YBH analyzed RNAseq data. TW and JMY provided patients samples. KLJ, XML, CW, TL and YBZ wrote, reviewed, and/or revised the manuscript. JMY, TL, YBZ, and JL contributed to the study supervision.

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Correspondence to Tao Liu, Jia Li or Yubo Zhou.

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Jiang, K., Li, X., Wang, C. et al. Dual inhibition of CHK1/FLT3 enhances cytotoxicity and overcomes adaptive and acquired resistance in FLT3-ITD acute myeloid leukemia. Leukemia 37, 539–549 (2023). https://doi.org/10.1038/s41375-022-01795-8

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