Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang, 110016, China; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China.
Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin, 300192, China.
Eur J Med Chem. 2022 Jan 5;227:113898. doi: 10.1016/j.ejmech.2021.113898. Epub 2021 Oct 9.
The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors have lower selectivity to PARP-1 than to PARP-2, so they will inevitably have side effects. Based on the different catalytic domains of PARP-1 and PARP-2, we developed a strategy to design and synthesize highly selective PARP-1 inhibitors. Compounds Y17, Y29, Y31 and Y49 showed excellent PARP-1 inhibition, and their IC values were 0.61, 0.66, 0.41 and 0.96 nM, respectively. Then, Y49 (PARP-1 IC = 0.96 nM, PARP-2 IC = 61.90 nM, selectivity PARP-2/PARP-1 = 64.5) was proved to be the most selective inhibitor of PARP-1. Compounds Y29 and Y49 showed stronger inhibitory effect on proliferation in BRCA1 mutant MX-1 cells than in other cancer cells. In the MDA-MB-436 xenotransplantation model, Y49 was well tolerated and showed remarkable single dose activity. The design strategy proposed in this paper is of far-reaching significance for the further construction of the next generation of selective PARP-1 inhibitors.
聚（ADP-核糖）聚合酶（PARP）抑制剂在癌症治疗中起着至关重要的作用。然而，大多数已批准的 PARP 抑制剂对 PARP-1 的选择性比对 PARP-2 的选择性低，因此它们不可避免地会有副作用。基于 PARP-1 和 PARP-2 的不同催化结构域，我们开发了一种设计和合成高选择性 PARP-1 抑制剂的策略。化合物 Y17、Y29、Y31 和 Y49 表现出优异的 PARP-1 抑制作用，其 IC 值分别为 0.61、0.66、0.41 和 0.96 nM。然后，Y49（PARP-1 IC = 0.96 nM，PARP-2 IC = 61.90 nM，PARP-2/PARP-1 的选择性 = 64.5）被证明是 PARP-1 最具选择性的抑制剂。化合物 Y29 和 Y49 在 BRCA1 突变型 MX-1 细胞中的增殖抑制作用强于其他癌细胞。在 MDA-MB-436 异种移植模型中，Y49 耐受性良好，单剂量活性显著。本文提出的设计策略对进一步构建下一代选择性 PARP-1 抑制剂具有深远的意义。
