Gynecologic oncology · 2025
G-M6, an oleanane triterpenoid, represents a novel scaffold for PARP1 inhibition and anticancer activity.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Ding Meng, Li Xu, Wang Hongling, Jia Xiaoqing, Gao Wenbin
Аннотация
BACKGROUND: The inhibition of Poly (ADP-ribose) polymerase 1 (PARP1) is a clinically validated strategy for treating cancers with homologous recombination (HR) deficiencies. Herein, we report the discovery and characterization of G-M6, a ginsenoside metabolite, as a novel PARP1 inhibitor.
METHODS AND RESULTS: G-M6 potently inhibited PARP1 in enzymatic assays with an IC50 of 12.38 nM, demonstrating a potency statistically comparable to the clinical inhibitor Olaparib (IC50 = 15.92 nM, p > 0.05). A screening assay against a panel of five kinases confirmed its selectivity for PARP1 over these specific off-targets. G-M6 induced a superior synthetic lethal effect in BRCA1-deficient UWB1.289 ovarian cancer cells (selectivity index = 4.70) compared to 2.88 for Olaparib. G-M6 also effectively sensitized HR-proficient cells to oxaliplatin and paclitaxel. In vivo, oral administration of G-M6 (80 mg/kg) produced robust tumor growth inhibition (TGI = 87.20 %) in a mouse xenograft model bearing HR-deficient UWB1.289 tumors, outperforming Olaparib (TGI = 86.53 %). This antitumor activity was specific, as no significant activity was observed in the HR-proficient SW620 model.
CONCLUSION: G-M6, a natural product-derived metabolite, was identified as a PARP1 inhibitor with enzymatic potency comparable to the approved drug Olaparib. The compound demonstrated synthetic lethality against HR-deficient cancer cells and reduced tumor growth in vivo. These findings, combined with its distinct natural product-derived chemical scaffold, highlight G-M6 as a promising lead compound for further preclinical investigation.
METHODS AND RESULTS: G-M6 potently inhibited PARP1 in enzymatic assays with an IC50 of 12.38 nM, demonstrating a potency statistically comparable to the clinical inhibitor Olaparib (IC50 = 15.92 nM, p > 0.05). A screening assay against a panel of five kinases confirmed its selectivity for PARP1 over these specific off-targets. G-M6 induced a superior synthetic lethal effect in BRCA1-deficient UWB1.289 ovarian cancer cells (selectivity index = 4.70) compared to 2.88 for Olaparib. G-M6 also effectively sensitized HR-proficient cells to oxaliplatin and paclitaxel. In vivo, oral administration of G-M6 (80 mg/kg) produced robust tumor growth inhibition (TGI = 87.20 %) in a mouse xenograft model bearing HR-deficient UWB1.289 tumors, outperforming Olaparib (TGI = 86.53 %). This antitumor activity was specific, as no significant activity was observed in the HR-proficient SW620 model.
CONCLUSION: G-M6, a natural product-derived metabolite, was identified as a PARP1 inhibitor with enzymatic potency comparable to the approved drug Olaparib. The compound demonstrated synthetic lethality against HR-deficient cancer cells and reduced tumor growth in vivo. These findings, combined with its distinct natural product-derived chemical scaffold, highlight G-M6 as a promising lead compound for further preclinical investigation.