CKD-9001的发现与表征：一种新型PARP1选择性抑制剂及DNA捕获剂，在HRD癌症中具有更强疗效和更优的毒性特征

Poly(ADP-ribose) polymerase (PARP) inhibitors have been established as therapeutic agents for patients with homologous recombination repair (HRR) deficiencies, such as BRCA1/2 mutations, in ovarian, breast, prostate, and pancreatic cancers. Currently, pan-PARP inhibitors that have received approval target both PARP1 and PARP2, demonstrating potent antitumor activity. However, PARP2 inhibition has been identified as a major contributor to hematologic toxicity, resulting in dose limitations and treatment discontinuation. Given PARP1's role as the primary enzyme in sensing single-strand breaks and regulating DNA repair processes, the development of PARP1-selective inhibitors has emerged as a promising strategy to achieve potent antitumor efficacy while minimizing toxicity compared with conventional pan-PARP inhibitors. In this study, we present the preclinical development of CKD-9001, a novel PARP1-selective inhibitor and potent DNA trapper.We developed CKD-9001, a next-generation PARP1-selective inhibitor, and evaluated its preclinical efficacy and toxicity profile against the leading agents, olaparib and saruparib. Our findings demonstrated excellent selectivity for PARP1, as evidenced by its high levels of enzymatic inhibition and DNA-trapping potency. In vitro studies demonstrated that CKD-9001 exhibited potent antiproliferative effects, with IC 50 values ≤10 nM in HRR-deficient and BRCA2-knockout cancer cell lines. In vivo studies showed remarkable antitumor efficacy of CKD-9001, even at low doses, in HRR-deficient animal models. Furthermore, pharmacokinetic and safety analyses confirmed that CKD-9001 markedly reduced hematologic toxicity and significantly improved the safety margin compared with conventional pan-PARP inhibitors. In addition, we found that CKD-9001 was capable of penetrating the blood-brain barrier (BBB).In conclusion, CKD-9001 is a next-generation PARP1-selective inhibitor that successfully combines enhanced efficacy with remarkably low toxicity, demonstrating outstanding therapeutic potential in HRD cancers.