Comparative safety, pharmacokinetics, and off-target assessment of 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane in mouse and dog: implications for therapeutic development.

Abstract

The modified phytochemical derivative, 1,1-bis(3'-indolyl)-1-(p-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.