Oncotarget

Research Papers:

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

Kazuhide Nakayama _, Magdalena M. Szewczyk, Carlo dela Sena, Hong Wu, Aiping Dong, Hong Zeng, Fengling Li, Renato Ferreira de Freitas, Mohammad S. Eram, Matthieu Schapira, Yuji Baba, Mihoko Kunitomo, Douglas R. Cary, Michiko Tawada, Akihiro Ohashi, Yasuhiro Imaeda, Kumar Singh Saikatendu, Charles E. Grimshaw, Masoud Vedadi, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy, Atsushi Kiba, Daisuke Tomita and Peter J. Brown

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Oncotarget. 2018; 9:18480-18493. https://doi.org/10.18632/oncotarget.24883

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Abstract

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

Correspondence to:

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

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.


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