Gai Renhua, Chen Chao, Zhang Wei, Ma Jian, Wang Xiaomeng, Chi Xiaoqing, Li Guangxing
College of Veterinary Medicine, Heilongjiang Key Laboratory for Animal and Comparative Medicine, Northeast Agricultural University, Harbin 150030, China.
Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Toxics. 2023 Oct 26;11(11):880. doi: 10.3390/toxics11110880.
Hu7691 represents a novel Pan-Akt kinase inhibitor, demonstrating excellent selectivity towards non-AGC kinase families and pronounced inhibitory effects on the proliferation of multiple tumor cell lines. However, there is currently a notable absence of in vivo toxicological research evidence concerning Hu7691. This study represents the first investigation into the 14-day repeated-dose toxicity of Hu7691 in male and female Sprague Dawley (SD) rats. Male rats were administered daily doses of 12.5, 50, 100, and 150 mg/kg/day, while female rats received doses of 12.5, 25, 50, and 75 mg/kg/day for 14 consecutive days. Hematological assessments, organ weights, and histopathological examinations revealed corresponding alterations, suggesting potential target organs for toxicity including the spleen, thymus, and gastrointestinal tract. It is worth noting that the test substance may also impact the liver, kidneys, heart, and ovaries. The No Observed Effect Level (NOAEL) was determined to be no greater than 12.5 mg/kg/day. Based on the observed gender-related toxicity differences in preliminary trials, it is recommended that the high dose reference dose for male animals in formal experiments should not be less than 100 mg/kg/day, while for female animals, it should be less than 50 mg/kg/day.
Hu7691是一种新型的泛Akt激酶抑制剂，对非AGC激酶家族表现出优异的选择性，并对多种肿瘤细胞系的增殖具有显著的抑制作用。然而，目前关于Hu7691的体内毒理学研究证据明显不足。本研究首次对Hu7691在雄性和雌性Sprague Dawley（SD）大鼠中的14天重复给药毒性进行了调查。雄性大鼠每日剂量为12.5、50、100和150 mg/kg/天，而雌性大鼠连续14天接受剂量为12.5、25、50和75 mg/kg/天的给药。血液学评估、器官重量和组织病理学检查显示了相应的变化，表明潜在的毒性靶器官包括脾脏、胸腺和胃肠道。值得注意的是，受试物质也可能影响肝脏、肾脏、心脏和卵巢。未观察到有害作用水平（NOAEL）被确定为不超过12.5 mg/kg/天。基于在初步试验中观察到的性别相关毒性差异，建议在正式实验中雄性动物的高剂量参考剂量不应低于100 mg/kg/天，而雌性动物的高剂量参考剂量应低于50 mg/kg/天。
