1. Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia.
- Author
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Guo Z, Zhang Z, Yang H, Cao D, Xu X, Zheng X, Chen D, Wang Q, Li Y, Li J, Du Z, Wang X, Chen L, Ding J, Shen J, Geng M, Huang X, and Xiong B
- Subjects
- Animals, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Chemistry Techniques, Synthetic, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacokinetics, G1 Phase Cell Cycle Checkpoints drug effects, Humans, Isoquinolines chemical synthesis, Isoquinolines chemistry, Isoquinolines pharmacokinetics, Isoquinolines pharmacology, Leukemia, Myeloid, Acute pathology, Mice, Models, Molecular, Protein Conformation, Protein-Arginine N-Methyltransferases chemistry, Stereoisomerism, Tissue Distribution, Xenograft Model Antitumor Assays, Drug Design, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Leukemia, Myeloid, Acute drug therapy, Protein-Arginine N-Methyltransferases antagonists & inhibitors
- 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. On the basis of 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 antitumor 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.
- Published
- 2019
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