TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma
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Kazuhide Nakayama1,*, Magdalena M. Szewczyk2,*, Carlo dela Sena2,*, Hong Wu2, Aiping Dong2, Hong Zeng2, Fengling Li2, Renato Ferreira de Freitas2, Mohammad S. Eram2, Matthieu Schapira2,3, Yuji Baba1, Mihoko Kunitomo1, Douglas R. Cary1, Michiko Tawada4, Akihiro Ohashi1, Yasuhiro Imaeda1, Kumar Singh Saikatendu5, Charles E. Grimshaw6, Masoud Vedadi2,3, Cheryl H. Arrowsmith2,7, Dalia Barsyte-Lovejoy2, Atsushi Kiba1, Daisuke Tomita1 and Peter J. Brown2
1Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan
2Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
3Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
4Medicinal Chemistry Research Laboratory, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan
5Structiural Biology, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, USA
6Enzymology and Biophysical Chemistry, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, USA
7Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada
*These authors have contributed equally to this work
Kazuhide Nakayama, email: [email protected]
Peter J. Brown, email: [email protected]
Keywords: PRMT4; small molecule inhibitor; TP-064; crystal structure; multiple myeloma
Received: November 11, 2017 Accepted: March 06, 2018 Published: April 06, 2018
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.
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