Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia

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Abstract
PRMT4 is a type I protein arginine methyltransferase and plays important roles in various cellular processes. Overexpression of PRMT4 has been found to be involved in several types of cancers. Selective and in vivo effective PRMT4 inhibitors are needed for demonstrating PRMT4 as a promising therapeutic target. Based on compound 6, a weak dual PRMT4/6 inhibitor, we constructed a tetrahydroisoquinoline scaffold through a cut-and-sew scaffold hopping strategy. The subsequent SAR optimization efforts employed structure-based approach led to the identification of a novel PRMT4 inhibitor 49. Compound 49 exhibited prominently high potency and selectivity, moderate pharmacokinetic profiles and good anti-tumor efficacy in acute myeloid leukemia xenograft model via oral administration, thus demonstrating this compound as a useful pharmacological tool for further target validation and drug development in cancer therapy.
Funding Information
  • National Natural Science Foundation of China (91853126)
  • Chinese Academy of Sciences (XDA12020371, XDA12020365)
  • Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning (2019CXJQ02)
  • National Science & Technology Major Project ?Key New Drug Creation and Manufacturing Program? of China (2018ZX09711002-004-002, 2018ZX09711002-004-014)
  • Natural Science Foundation of China for Innovation Research Group (81821005)
  • Shanghai Talent Development Founds (201663)

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