1. TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma
- Author
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Dalia Barsyte-Lovejoy, Yuji Baba, Peter Brown, Atsushi Kiba, Daisuke Tomita, Douglas R. Cary, Aiping Dong, Hong Zeng, Mihoko Kunitomo, Kazuhide Nakayama, Cheryl H. Arrowsmith, Fengling Li, Matthieu Schapira, Mohammad S. Eram, Charles E. Grimshaw, Yasuhiro Imaeda, Carlo C. dela Seña, Kumar Singh Saikatendu, Hong Wu, Akihiro Ohashi, Michiko Tawada, Renato Ferreira de Freitas, Magdalena M. Szewczyk, and Masoud Vedadi
- Subjects
0301 basic medicine ,crystal structure ,Methyltransferase ,Arginine ,CARM1 ,Chemistry ,Protein subunit ,small molecule inhibitor ,Cell cycle ,TP-064 ,Small molecule ,3. Good health ,multiple myeloma ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Biochemistry ,Cell culture ,030220 oncology & carcinogenesis ,PRMT4 ,IC50 ,Research Paper - Abstract
Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as a candidate oncogene owing to its overexpression in several types of cancer. Selective PRMT4 inhibitors are useful tools for clarifying the molecular events regulated by PRMT4 and for validating PRMT4 as a therapeutic target. Here, we report the discovery of TP-064, a potent, selective, and cell-active chemical probe of human PRMT4 and its co-crystal structure with PRMT4. TP-064 inhibited the methyltransferase activity of PRMT4 with high potency (half-maximal inhibitory concentration, IC50 < 10 nM) and selectivity over other PRMT family proteins, and reduced arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155; IC50= 340 ± 30 nM) and Mediator complex subunit 12 (MED12; IC50 = 43 ± 10 nM). TP-064 treatment inhibited the proliferation of a subset of multiple myeloma cell lines, with affected cells arrested in G1 phase of the cell cycle. TP-064 and its negative control (TP-064N) will be valuable tools to further investigate the biology of PRMT4 and the therapeutic potential of PRMT4 inhibition.
- Published
- 2018