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Oncotarget. 2018 Apr 6;9(26):18480-18493. doi: 10.18632/oncotarget.24883. eCollection 2018 Apr 6.

TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma.

Author information

1
Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
2
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
3
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
4
Medicinal Chemistry Research Laboratory, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa 251-8555, Japan.
5
Structiural Biology, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
6
Enzymology and Biophysical Chemistry, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
7
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
#
Contributed equally

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.

KEYWORDS:

PRMT4; TP-064; crystal structure; multiple myeloma; small molecule inhibitor

Conflict of interest statement

CONFLICTS OF INTEREST KN, DT, DC, YB, MK, AK, AO, MT, KS and CG are employees of Takeda Pharmaceutical Company. CS, FL, RFF, MSE, MS (Szewczyk), MV, CHA, PJB, HW, DB-L, HZ, MS (Schapira) and AD are employees of the University of Toronto. The Structural Genomics Consortium is funded in part by Takeda.

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