6IZQ

PRMT4 bound with a bicyclic compound

Summary for 6IZQ

• Entry DOI: 10.2210/pdb6izq/pdb
• Descriptor: Histone-arginine methyltransferase CARM1, (2R)-1-(methylamino)-3-(1,3,4,5-tetrahydro-2-benzazepin-2-yl)propan-2-ol (3 entities in total)
• Functional Keywords: histone-arginine methyltransferase carm1, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 151767.51

Authors

Xiong, B.,Cao, D.Y.,Guo, Z.H.,Li, Y.L.,Li, J.,Huang, X.,Shen, J.K. (deposition date: 2018-12-20, release date: 2019-12-25, Last modification date: 2024-03-27)

Primary citation

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.,Xiong, B.
Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia.
J.Med.Chem., 62:5414-5433, 2019

PubMed 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.

PubMed: 31117515
DOI: 10.1021/acs.jmedchem.9b00297

Experimental method

X-RAY DIFFRACTION (2.449 Å)