TAS1553

Cell lines

Human cancer cell lines (HCC38 breast cancer, MV-4-11 acute myelogenous leukemia)

Preparation Method

Cells were maintained in RPMI-1640 or DMEM supplemented with 10% fetal bovine serum (FBS) at 37°C, 5% CO₂. Cells were treated with TAS1553 at concentrations ranging from 0.228 to 10μmol/L for 30 minutes to 24 hours.

Reaction Conditions

0.228–10μmol/L; 30min–24h

Applications

TAS1553 significantly reduced the intracellular dATP pool by disrupting the protein-protein interaction between RNR subunits R1 and R2, leading to DNA replication stress and replication fork stalling. This was accompanied by phosphorylation of Chk1 (Ser345) and RPA2 (Ser4/Ser8, Thr21) within 2 hours. TAS1553 induced apoptosis via caspase-3/7 activation and PARP cleavage, with efficacy strongly correlated with SLFN11 expression levels.

Animal models

F344/NJcl-mu/rnu rats bearing MV-4-11 xenografts, BALB/cAJcl-nu/nu mice bearing HCC38 xenografts, and B6N-Tyrc-Brd/BrdCrCrl mice with systemic MLL-AF9-driven acute myelogenous leukemia (AML).

Preparation Method

Rats and mice were subcutaneously implanted with tumor cells or intravenously inoculated with AML cells. TAS1553 was administered orally once daily at doses of 50–400mg/kg for 14–21 days. For pharmacodynamic studies, tumors were collected at 1, 2, and 4 hours after a single oral dose.

Dosage form

50–400mg/kg; p.o.; Once daily for 14–21 days

Applications

TAS1553 administration significantly suppressed tumor growth in MV-4-11 xenografts and induced complete tumor regression at 400mg/kg. TAS1553 reduced intratumoral dATP pools within 1–2 hours, triggered DNA replication stress (phospho-Chk1 elevation), and activated apoptosis (cleaved PARP and caspase-3). In the systemic AML model, TAS1553 (100mg/kg) extended median survival by 34.8%. Body weight remained stable, indicating tolerability.

References:
[1] Ueno H, Hoshino T, Yano W, et al. 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.