TAS1553, a small molecule subunit interaction inhibitor of ribonucleotide reductase, exhibits antitumor activity by causing DNA replication stress

  • Commun Biol. 2022 Jun 9;5(1):571. doi: 10.1038/s42003-022-03516-4.
Hiroyuki Ueno   #  1 ,  Takuya Hoshino  2 ,  Wakako Yano  2 ,  Sayaka Tsukioka  2 ,  Takamasa Suzuki  2 ,  Shoki Hara  2 ,  Yoshio Ogino  2 ,  Khoon Tee Chong  2 ,  Tatsuya Suzuki  2 ,  Shingo Tsuji  2 ,  Hikaru Itadani  2 ,  Ikuo Yamamiya  2 ,  Yoshihiro Otsu  2 ,  Satoshi Ito  2 ,  Toshiya Yonekura  2 ,  Miki Terasaka  2 ,  Nozomu Tanaka  2 ,  Seiji Miyahara   #  3
Affiliations
  • 1. Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. [email protected].
  • 2. Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan.
  • 3. Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. [email protected].
  • # Contributed equally.
PMID: 35681099 DOI: 10.1038/s42003-022-03516-4
Abstract

Ribonucleotide reductase (RNR) is composed of two non-identical subunits, R1 and R2, and plays a crucial role in balancing the cellular dNTP pool, establishing it as an attractive Cancer target. Herein, we report the discovery of a highly potent and selective small-molecule inhibitor, TAS1553, targeting protein-protein interaction between R1 and R2. TAS1553 is also expected to demonstrate superior selectivity because it does not directly target free radical or a substrate binding site. TAS1553 has shown antiproliferative activity in human Cancer cell lines, dramatically reducing the intracellular dATP pool and causing DNA replication stress. Furthermore, we identified SLFN11 as a biomarker that predicts the cytotoxic effect of TAS1553. Oral administration of TAS1553 demonstrated robust antitumor efficacy against both hematological and solid Cancer xenograft Tumors and also provided a significant survival benefit in an acute myelogenous leukemia model. Our findings strongly support the evaluation of TAS1553 in clinical trials.

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