DataSheet1_Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305.PDF

The family of poly (ADP-ribose) polymerases (PARPs) consists of 17 members, which have been demonstrated as having effects on a series of cellular processes, including DNA replication and repair. PARP inhibitors (PARPi) suppress DNA repair through “PARP trapping”, thus, constitute an important treatment option for cancer nowadays. In addition, PARP inhibition and homologous recombination repair (HRR) defects are synthetically lethal, giving a promising therapeutic for homologous recombination repair deficient (HRD) tumors including BRCA mutation. However, overlapping hematologic toxicity causes PARPi to fail in combination with some first-line chemotherapies. Furthermore, recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for antitumor activity in HRD cancer models. Currently approved PARPi have shown varying levels of selectivity for the entire 17-member PARP family, hence contribute to toxicity. Together, these findings above have provided the necessity and feasibility of developing next-generation PARPi with improved selectivity for PARP1, expanding significant clinical values and wide application prospects both in monotherapy and combination with other anticancer agents. In this review, we summery the latest research of current approved PARPi, discuss the current status and future promise of next-generation PARP1-selective inhibitor AZD5305, including its reported progress up to now and anticipated impact on clinical.

聚ADP-核糖聚合酶（poly (ADP-ribose) polymerases, PARPs）家族包含17个成员，现已被证实参与诸多细胞进程，包括DNA复制与修复。PARP抑制剂（PARP inhibitors, PARPi）通过“PARP捕获”机制抑制DNA修复，因此目前已成为重要的癌症治疗选择。此外，PARP抑制与同源重组修复（homologous recombination repair, HRR）缺陷存在合成致死效应，可为包括BRCA突变在内的同源重组修复缺陷（homologous recombination repair deficient, HRD）肿瘤带来极具前景的治疗方案。然而，重叠的血液学毒性导致PARPi无法与部分一线化疗药物联合使用。近期研究进一步表明，PARP1抑制与PARP1-DNA捕获是HRD癌症模型中抗肿瘤活性的关键机制。当前获批的PARPi对全部17个PARP家族成员展现出不同程度的选择性，这也是其产生毒性的重要原因。综上，上述研究成果凸显了开发选择性更优的下一代PARP1选择性抑制剂的必要性与可行性，这类药物在单药治疗以及与其他抗肿瘤药物联合应用领域均具备重要临床价值与广阔应用前景。在本综述中，我们总结了当前获批PARPi的最新研究进展，探讨了下一代PARP1选择性抑制剂AZD5305的现状与未来前景，包括其迄今已报道的研究进展以及对临床应用的预期影响。