Abstract 7132: Preclinical characterization of LAE119, a novel PARP1 selective inhibitor and trapper

作者：Ming Li, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Justin Gu · 发表于：Cancer Research · 年份：2024 · DOI：10.1158/1538-7445.am2024-7132 · 被引用次数：2 · 研究领域：PARP inhibition in cancer therapy

Abstract Current PARP inhibitors primarily target PARP1/2 and demonstrate high efficacy against tumors with deficiencies in homologous recombination repair, such as those with BRCA mutations. However, these inhibitors are also associated with significant hematological toxicities. Studies have indicated that the synthetic lethality observed with BRCA mutations is mainly driven by PARP1, while PARP2 is not essential in this context. PARP2 has been shown to be crucial for the survival of hematopoietic stem/progenitor cells in animal models. Therefore, selective inhibition of PARP1 could potentially reduce toxicity and improve therapeutic outcomes. Here we introduce LAE119, a potent and selective PARP1 inhibitor and PARP1-DNA trapper. It demonstrates more than a 1000-fold selectivity for PARP1 DNA trapping compared to PARP2. In comparison to most PARP inhibitors including AZD5305, LAE119 exhibits extremely long residence time on PARP1 in both biochemical and cellular assays. It demonstrates robust anti-proliferation activity against BRCA2−/− DLD-1 cells and MDA-MB-436 cells, with IC50 value of 0.6 nM in both cell lines. In CAL51 cells, which has a BRCA2 mutation but with low PARP1 expression level and are much less sensitive to AZD5305, LAE119 demonstrates much better activity than AZD5305, particularly when PARP1 level is increased with transgene expression. LAE119 demonstrated substantial tumor inhibition in MDA-MB-436 and Capan-1 xenograft models. LAE119 also displays favorabl...