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Updated: Sep 20, 2025

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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TAS1553, a small molecule subunit interaction inhibitor of ribonucleotide reductase, exhibits antitumor activity by

Hiroyuki Ueno1, Takuya Hoshino2, Wakako Yano2

  • 1Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. h-ueno@taiho.co.jp.

Communications Biology
|June 10, 2022
PubMed

Insights

A new drug, TAS1553, inhibits ribonucleotide reductase (RNR) by targeting its R1 and R2 subunits. This cancer drug shows potent antiproliferative activity and antitumor efficacy, supporting clinical trials.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Ribonucleotide reductase (RNR) is essential for DNA synthesis, regulating the cellular dNTP pool.
  • RNR's critical role in cell proliferation makes it a promising cancer therapeutic target.

Purpose of the Study:

  • To discover and characterize TAS1553, a novel small-molecule inhibitor targeting the RNR R1-R2 protein-protein interaction.
  • To evaluate the preclinical efficacy and identify biomarkers for TAS1553 in cancer models.

Main Methods:

  • Small-molecule screening to identify TAS1553.
  • In vitro assays to assess antiproliferative activity and dNTP pool reduction.
  • In vivo studies using cancer xenograft models and biomarker analysis (SLFN11).

Main Results:

  • TAS1553 potently inhibits RNR by disrupting R1-R2 interaction, showing superior selectivity.
  • TAS1553 demonstrated significant antiproliferative effects in cancer cell lines, reducing dATP levels and inducing DNA replication stress.
  • SLFN11 was identified as a predictive biomarker for TAS1553's cytotoxic effects.
  • Oral TAS1553 exhibited robust antitumor efficacy in hematological and solid tumor xenografts, improving survival in AML models.

Conclusions:

  • TAS1553 is a potent and selective RNR inhibitor with promising preclinical antitumor activity.
  • The identification of SLFN11 as a predictive biomarker facilitates patient stratification for potential clinical trials.
  • TAS1553 warrants further clinical investigation as a novel cancer therapeutic agent.

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