TAS1553 is a small-molecule protein-protein interaction inhibitor that effectively suppresses the activity of ribonucleotide reductase (RNR). By disrupting the DNA replication process and reducing intracellular deoxyadenosine triphosphate (dATP) levels, TAS1553 ultimately induces apoptosis[1].
In vitro, treatment of human cancer cell lines (HCC38 and MV-4-11) with TAS1553 (0.228–10μmol/L) for 30 minutes to 24 hours significantly depletes the intracellular dATP pool, induces DNA replication stress and replication fork stalling, and leads to apoptotic cell death[1].
In vivo, oral administration of TAS1553 (50–400mg/kg) once daily for 14–21 days in female NOD/SCID mice bearing MV-4-11 xenografts significantly suppresses tumor growth and promotes tumor regression. This is accompanied by reduced intratumoral dATP levels and activation of replication stress and apoptotic pathways [1].
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.
TAS1553是一种小分子蛋白-蛋白相互作用抑制剂，能有效抑制核糖核苷酸还原酶（RNR）的活性。TAS1553干扰DNA复制过程并减少细胞内脱氧腺苷三磷酸（dATP）的水平，最终诱导细胞凋亡[1]。
在体外，TAS1553（0.228–10μmol/L）处理人癌症细胞系（如HCC38和MV-4-11）30分钟至24小时，TAS1553显著降低细胞内脱氧腺苷三磷酸（dATP）库，并诱导DNA复制应激及复制叉停滞，最终导致细胞凋亡[1]。
在体内，TAS1553（50–400mg/kg）每日一次口服给药，用于处理携带MV-4-11异种移植瘤的雌性NOD/SCID小鼠，持续14-21天。TAS1553显著抑制肿瘤生长并诱导肿瘤消退，同时降低肿瘤内dATP库并激活复制应激与凋亡通路[1]。