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

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

  • Oncotarget. 2018 Apr 6;9(26):18480-18493. doi: 10.18632/oncotarget.24883.
Kazuhide Nakayama  # 1,  Magdalena M Szewczyk  # 2,  Carlo Dela Sena  # 2,  Hong Wu 2,  Aiping Dong 2,  Hong Zeng 2,  Fengling Li 2,  Renato Ferreira de Freitas 2,  Mohammad S Eram 2,  Matthieu Schapira 2 3,  Yuji Baba 1,  Mihoko Kunitomo 1,  Douglas R Cary 1,  Michiko Tawada 4,  Akihiro Ohashi 1,  Yasuhiro Imaeda 1,  Kumar Singh Saikatendu 5,  Charles E Grimshaw 6,  Masoud Vedadi 2 3,  Cheryl H Arrowsmith 2 7,  Dalia Barsyte-Lovejoy 2,  Atsushi Kiba 1,  Daisuke Tomita 1,  Peter J Brown 2
Affiliations

Affiliations

  • 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.
PMID: 29719619 DOI: 10.18632/oncotarget.24883
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.

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