2. Academic Validation
  3. Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities

Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities

  • J Med Chem. 2023 Sep 14;66(17):11792-11814. doi: 10.1021/acs.jmedchem.3c00245.
Xuemei Li 1,  Peipei Wang 2,  Chang Wang 3,  Tingting Jin 4,  Ran Xu 2,  Lexian Tong 1 5,  Xiaobei Hu 3 6,  Liteng Shen 7,  Jia Li 2 3 6,  Yubo Zhou 2 3 6,  Tao Liu 1 7
Affiliations

Affiliations

  • 1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P.R. China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China.
  • 4 Department of Clinical Pharmacy, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou310006, P.R. China.
  • 5 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, P. R. China.
  • 6 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan Tsuihang New District,Guangdong 528400, P. R. China.
  • 7 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou310058, P.R. China.
PMID: 37584545 DOI: 10.1021/acs.jmedchem.3c00245
Abstract

FLT3 inhibitors as single agents have limited effects because of acquired and adaptive resistance and the cardiotoxicity related to human ether-a-go-go-related gene (hERG) channel blockade further impedes safe drugs to the market. Inhibitors having potential to overcome resistance and reduce hERG affinity are highly demanded. Here, we reported a dual FLT3/Chk1 Inhibitor 18, which displayed potencies to overcome varying acquired resistance in BaF3 cells with FLT3-TKD and FLT3-ITD-TKD mutations. Moreover, 18 displayed high selectivity over c-Kit more than 1700-fold and greatly reduced hERG affinity, with an IC50 value of 58.4 μM. Further mechanistic studies demonstrated 18 can upregulate p53 and abolish the outgrowth of adaptive resistant cells. In the in vivo studies, 18 demonstrated favorable PK profiles and good safety, suppressed the tumor growth in the MV-4-11 cell inoculated mouse xenograft model, and prolonged the survival in the Molm-13 transplantation model, supporting its further development.

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