The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models
The PARP Inhibitor AZD2461 Provides Insights into the Role of PARP3 Inhibition for Both Synthetic Lethality and Tolerability with Chemotherapy in Preclinical Models
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DOI：
10.1158/0008-5472.can-15-3240
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发表时间：
2016-10-01
期刊：
影响因子：
11.2
通讯作者：
O'Connor, Mark J.
中科院分区：
文献类型：
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作者：
O'Connor, Lenka Oplustil;Rulten, Stuart L.;O'Connor, Mark J.
PARP抑制剂AZD 2461是继奥拉帕尼（第一个批准用于癌症治疗的PARP抑制剂）之后开发的下一代药物。在BRCA 1缺陷小鼠模型中，奥拉帕尼耐药主要涉及P-糖蛋白的过表达，因此AZD 2461被开发为药物转运蛋白的不良底物。在这里，我们证明了这种化合物对过表达P-糖蛋白的奥拉帕尼耐药肿瘤的疗效。此外，AZD 2461与化疗联合使用在小鼠中的耐受性比奥拉帕尼更好，这表明AZD 2461在临床上可能比奥拉帕尼具有显着优势。然而，这种上级毒性特征并未延伸至大鼠。对这种差异的研究表明，与大鼠和人相比，每种化合物的PARP 3抑制活性不同，小鼠骨髓细胞中的PARP 3表达水平更高。我们的研究结果对使用小鼠模型评估DNA损伤剂和DNA损伤反应抑制剂的骨髓毒性具有影响。最后，用不同PARP抑制剂对PARP 3活性位点进行结构建模也突出了开发具有不同PARP家族成员特异性特征的化合物以获得最佳抗肿瘤活性和耐受性的潜力。(C)2016年AACR。
The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein, so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability. (C) 2016 AACR.