2. Academic Validation
  3. Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML)

Discovery of a highly potent kinase inhibitor capable of overcoming multiple imatinib-resistant ABL mutants for chronic myeloid leukemia (CML)

  • Eur J Pharmacol. 2021 Apr 15;897:173944. doi: 10.1016/j.ejphar.2021.173944.
Tingting Lu 1,  Jiangyan Cao 2,  Fengming Zou 3,  Xixiang Li 3,  Aoli Wang 3,  Wenliang Wang 4,  Huamin Liang 3,  Qingwang Liu 3,  Chen Hu 3,  Cheng Chen 4,  Zhenquan Hu 4,  Wenchao Wang 3,  Lili Li 5,  Jian Ge 5,  Yang Shen 6,  Tao Ren 4,  Jing Liu 2,  Ruixiang Xia 7,  Qingsong Liu 8
Affiliations

Affiliations

  • 1 Anhui Province Key Laboratory of Medical Physics and Technology; CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, PR China.
  • 2 Anhui Province Key Laboratory of Medical Physics and Technology; CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China.
  • 3 Anhui Province Key Laboratory of Medical Physics and Technology; CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
  • 4 Anhui Province Key Laboratory of Medical Physics and Technology; CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China.
  • 5 Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, PR China.
  • 6 The First Hospital of Jiaxing, 1882 Zhonghuan South Rd, Jiaxing, Zhejiang, 314000, PR China.
  • 7 Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, PR China. Electronic address: xrx2041@163.com.
  • 8 Anhui Province Key Laboratory of Medical Physics and Technology; CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology; Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; University of Science and Technology of China, Hefei, Anhui, 230026, PR China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, PR China; Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, PR China; Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, PR China. Electronic address: qsliu97@hmfl.ac.cn.
PMID: 33581133 DOI: 10.1016/j.ejphar.2021.173944
Abstract

As the critical driving force for chronic myeloid leukemia (CML), BCR gene fused ABL kinase has been extensively explored as a validated target of drug discovery. Although imatinib has achieved tremendous success as the first-line treatment for CML, the long-term application ultimately leads to resistance, primarily via various acquired mutations occurring in the Bcr-Abl kinase. Although dasatinib and nilotinib have been approved as second-line therapies that could overcome some of these mutants, the most prevalent gatekeeper T315I mutant remains unconquered. Here, we report a novel type II kinase inhibitor, CHMFL-48, that potently inhibits the wild-type Bcr-Abl (wt) kinase as well as a panel of imatinib-resistant mutants, including T315I, F317L, E255K, Y253F, and M351T. CHMFL-48 displayed great inhibitory activity against ABL wt (IC50: 1 nM, 70-fold better than imatinib) and the ABL T315I mutant (IC50: 0.8 nM, over 10,000-fold better than imatinib) in a biochemical assay and potently blocked the autophosphorylation of Bcr-Abl wt and Bcr-Abl mutants in a cellular context, which further affected downstream signalling mediators, including signal transducer and activator of transcription 5 (STAT5) and CRK like proto-oncogene (CRKL), and led to the cell cycle progression blockage as well as Apoptosis induction. CHMFL-48 also exhibited great anti-leukemic efficacies in vivo in K562 cells and p210-T315I-transformed BaF3 cell-inoculated murine models. This discovery extended the pharmacological diversity of Bcr-Abl kinase inhibitors and provided more potential options for anti-CML therapies.

Keywords

ABL mutants; BCR-ABL; Chronic myeloid leukemia; Imatinib resistance; Kinase inhibitor.

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