1. Academic Validation
  2. 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.
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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