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Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia
- Source :
- Journal of medicinal chemistry. 62(11)
- Publication Year :
- 2019
-
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.
- Subjects :
- Models, Molecular
Protein-Arginine N-Methyltransferases
Protein Conformation
Apoptosis
Stereoisomerism
Chemistry Techniques, Synthetic
Isoquinolines
G1 Phase Cell Cycle Checkpoints
Xenograft Model Antitumor Assays
Leukemia, Myeloid, Acute
Mice
Cell Line, Tumor
Drug Design
Drug Discovery
Molecular Medicine
Animals
Humans
Tissue Distribution
Enzyme Inhibitors
Cell Proliferation
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 62
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....d70ddca7b7faefecb5db90d29c25a6f8