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

Authors

• Savannah M. Rocha, Department of Environmental and Radiological Health Sciences, Colorado State University, 1680 Campus Delivery Fort Collins, CO 80523, USA.
• Daniel L. Gustafson, Department of Clinical Sciences, Colorado State University, 1678 Campus Delivery Fort Collins, CO 80523, USA.
• Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M School of Veterinary, Medicine & Biomedical Sciences, 4466 TAMU College Station, TX 77843-4466, USA.
• Ronald B. Tjalkens, Department of Environmental and Radiological Health Sciences, Colorado State University, 1680 Campus Delivery Fort Collins, CO 80523, USA.

Document Type

Article

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.

Keywords

1, 1-bis(3′-indolyl)-1-(p-chlorophenyl) methane, cancer, neurodegeneration, off-target binding, pharmacokinetics, preclinical safety

Publication Date

4-1-2024

Publication Title

Toxicology research

ISSN

2045-452X

Volume

13

Issue

2

First Page

tfae059

PubMed ID

38655145

Digital Object Identifier (DOI)

10.1093/toxres/tfae059

Recommended Citation

Rocha, Savannah M.; Gustafson, Daniel L.; Safe, Stephen; and Tjalkens, Ronald B., "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" (2024). Translational Neuroscience. 2511.
https://scholar.barrowneuro.org/neurobiology/2511