Examination of Diazaspiro Cores as Piperazine Bioisosteres in the Olaparib Framework Shows Reduced DNA Damage and Cytotoxicity

Development of poly­(ADP-ribose)
polymerase inhibitors (PARPi’s)
continues to be an attractive area of research due to synthetic lethality
in DNA repair deficient cancers; however, PARPi’s also have
potential as therapeutics to prevent harmful inflammation. We investigated
the pharmacological impact of incorporating spirodiamine motifs into
the phthalazine architecture of FDA approved PARPi olaparib. Synthesized
analogues were screened for PARP-1 affinity, enzyme specificity, catalytic
inhibition, DNA damage, and cytotoxicity. This work led to the identification
of 10e (12.6 ± 1.1 nM), which did not induce DNA
damage at similar drug concentrations as olaparib. Interestingly,
several worst in class compounds with low PARP-1 affinity, including 15b (4397 ± 1.1 nM), induced DNA damage at micromolar
concentrations, which can explain the cytotoxicity observed in vitro.
This work provides further evidence that high affinity PARPi’s
can be developed without DNA damaging properties offering potential
new drugs for treating inflammatory related diseases.

聚ADP核糖聚合酶抑制剂（poly(ADP-ribose) polymerase inhibitors，以下简称PARPi）的研发仍是极具吸引力的研究方向，因其可在DNA修复缺陷型癌症中发挥合成致死效应；然而，PARPi亦具备作为治疗药物阻断有害炎症的潜力。本研究探究了将螺二胺基序引入FDA已获批的PARPi奥拉帕利（olaparib）的酞嗪骨架后，对其药理学特性的影响。我们对合成得到的结构类似物进行了PARP-1结合亲和力、酶特异性、催化抑制活性、DNA损伤及细胞毒性的筛选。本研究最终鉴定出化合物10e（12.6 ± 1.1 nM），其在与奥拉帕利相当的药物浓度下不会诱导DNA损伤。值得注意的是，多款PARP-1结合亲和力较低的同类表现最差化合物（包括化合物15b，4397 ± 1.1 nM）可在微摩尔浓度下诱导DNA损伤，这可解释体外实验中观测到的细胞毒性现象。本研究进一步证实，可开发出不具备DNA损伤特性的高亲和力PARPi，为炎症相关疾病的治疗提供了潜在的新型治疗药物。