Rocha Savannah M, Gustafson Daniel L, Safe Stephen, Tjalkens Ronald B
Department of Environmental and Radiological Health Sciences, Colorado State University, 1680 Campus Delivery Fort Collins, CO 80523, USA.
Department of Clinical Sciences, Colorado State University, 1678 Campus Delivery Fort Collins, CO 80523, USA.
Toxicol Res (Camb). 2024 Apr 21;13(2):tfae059. doi: 10.1093/toxres/tfae059. eCollection 2024 Apr.
The modified phytochemical derivative, 1,1-bis(3'-indolyl)-1-(-chlorophenyl) methane (C-DIM12), has been identified as a potential therapeutic platform based on its capacity to improve disease outcomes in models of neurodegeneration and cancer. However, comprehensive safety studies investigating pathology and off-target binding have not been conducted. To address this, we administered C-DIM12 orogastrically to outbred male CD-1 mice for 7 days (50 mg/kg/day, 200 mg/kg/day, and 300 mg/kg/day) and investigated changes in hematology, clinical chemistry, and whole-body tissue pathology. We also delivered a single dose of C-DIM12 (1 mg/kg, 5 mg/kg, 25 mg/kg, 100 mg/kg, 300 mg/kg, 1,000 mg/kg) orogastrically to male and female beagle dogs and investigated hematology and clinical chemistry, as well as plasma pharmacokinetics over 48-h. Consecutive in-vitro off-target binding through inhibition was performed with 10 μM C-DIM12 against 68 targets in tandem with predictive off-target structural binding capacity. These data show that the highest dose C-DIM12 administered in each species caused modest liver pathology in mouse and dog, whereas lower doses were unremarkable. Off-target screening and predictive modeling of C-DIM12 show inhibition of serine/threonine kinases, calcium signaling, G-protein coupled receptors, extracellular matrix degradation, and vascular and transcriptional regulation pathways. Collectively, these data demonstrate that low doses of C-DIM12 do not induce pathology and are capable of modulating targets relevant to neurodegeneration and cancer.
改良的植物化学衍生物1,1-双（3'-吲哚基）-1-（-氯苯基）甲烷（C-DIM12），因其在神经退行性疾病和癌症模型中改善疾病结局的能力，已被确定为一个潜在的治疗平台。然而，尚未进行全面的安全性研究来调查病理学和脱靶结合情况。为了解决这个问题，我们对远交系雄性CD-1小鼠经口胃内给予C-DIM12，持续7天（50毫克/千克/天、200毫克/千克/天和300毫克/千克/天），并研究血液学、临床化学和全身组织病理学的变化。我们还对雄性和雌性比格犬经口胃内给予单次剂量的C-DIM12（1毫克/千克、5毫克/千克、25毫克/千克、100毫克/千克、300毫克/千克、1000毫克/千克），并研究血液学和临床化学，以及48小时内的血浆药代动力学。用10μM C-DIM12针对68个靶点进行连续的体外抑制性脱靶结合，并结合预测性脱靶结构结合能力进行研究。这些数据表明，在每个物种中给予的最高剂量的C-DIM12在小鼠和犬中引起了轻微的肝脏病理学变化，而较低剂量则无明显影响。C-DIM12的脱靶筛选和预测模型显示其对丝氨酸/苏氨酸激酶、钙信号传导、G蛋白偶联受体、细胞外基质降解以及血管和转录调控途径有抑制作用。总的来说，这些数据表明低剂量的C-DIM12不会诱导病理学变化，并且能够调节与神经退行性疾病和癌症相关的靶点。
