Talazoparib tosylate (BMN 673ts) 是一种新型，高效，有可口服活性的 PARP1/2 抑制剂，抑制PARP1的IC50 值为 0.57 nM。
Talazoparib tosylate (BMN 673ts) is a novel, potent and orally available PARP1/2 inhibitor with an IC50 of 0.57 nM for PARP1. IC50: 0.57 nM (PARP1)[1]
Talazoparib is a potent PARP1/2 inhibitor (PARP1 IC50=0.57 nM), it has no effect on PARG activity at concentrations up to 1 μM. Talazoparib binds to PARP1 with a dissociation constant (KD) of 0.29 nM. Talazoparib inhibits PARP1 and -2 to a similar extent, with Kis of 1.20 and 0.85 nM, respectively. Talazoparib selectively targets tumor cells with BRCA1, BRCA2, or PTEN gene defects with 20- to more than 200-fold greater potency than existing PARP1/2 inhibitors. Talazoparib targets tumor cells with homologous recombination gene defects. Tumor models that are either BRCA1-deficient (MX-1 and SUM149) or BRCA2-deficient (Capan-1) are profoundly sensitive to Talazoparib. Talazoparib induces nuclear γ-H2AX foci at concentrations as low as 100 pM[1].
Talazoparib is readily orally bioavailable, with more than 40% absolute oral bioavailability in rats when dosed in carboxylmethyl cellulose. Oral administration of Talazoparib elicits remarkable antitumor activity; xenografted tumors that carry defects in DNA repair due to BRCA mutations or PTEN deficiency are profoundly sensitive to oral Talazoparib treatment at well-tolerated doses in mice. Synergistic or additive antitumor effects are also found when Talazoparib is combined with temozolomide, SN38, or platinum drugs[1].
Talazoparib tosylate (BMN 673ts) 是一种新型、有效且可口服的 PARP1/2 抑制剂，对 PARP1 的 IC50 为 0.57 nM。 IC50:0.57 nM (PARP1)[1]
Talazoparib 是一种有效的 PARP1/2 抑制剂（PARP1 IC50=0.57 nM），它在浓度高达 1 μM 时对 PARG 活性没有影响。 Talazoparib 以 0.29 nM 的解离常数 (KD) 结合 PARP1。 Talazoparib 以相似的程度抑制 PARP1 和 -2，Kis 分别为 1.20 和 0.85 nM。 Talazoparib 选择性靶向具有 BRCA1、BRCA2 或 PTEN 基因缺陷的肿瘤细胞，效力比现有的 PARP1/2 抑制剂高 20 至 200 多倍。 Talazoparib 靶向具有同源重组基因缺陷的肿瘤细胞。 BRCA1 缺陷（MX-1 和 SUM149）或 BRCA2 缺陷（Capan-1）的肿瘤模型对 Talazoparib 极为敏感。 Talazoparib 在低至 100 pM 的浓度下诱导核 γ-H2AX 灶[1]。
Talazoparib 具有口服生物利用度，当以羧甲基纤维素给药时，大鼠的绝对口服生物利用度超过 40%。 Talazoparib 的口服给药具有显着的抗肿瘤活性；由于 BRCA 突变或 PTEN 缺陷而携带 DNA 修复缺陷的异种移植肿瘤对小鼠口服耐受良好剂量的 Talazoparib 治疗非常敏感。 Talazoparib 与替莫唑胺、SN38 或铂类药物联合使用时，也发现了协同或相加的抗肿瘤作用[1]。
[1]. Shen Y, et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res. 2013 Sep 15;19(18):5003-15.
动态评分
0.0