In vitro safety signals for potential clinical development of the anti-inflammatory pregnane X receptor agonist FKK6

Dvořák, Zdeněk; Vyhlídalová, Barbora; Pečinková, Petra; Li, Hao; Anzenbacher, Pavel; Špičáková, Alena; Anzenbacherová, Eva; Chow, Vimanda; Liu, Jiabao; Krause, Henry; Wilson, Derek; Berés, Tibor; Tarkowski, Petr; Chen, Dajun; Mani, Sridhar

doi:10.1016/j.bioorg.2024.107137

Bioorganic Chemistry

2024

DOI: 10.1016/j.bioorg.2024.107137

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In vitro safety signals for potential clinical development of the anti-inflammatory pregnane X receptor agonist FKK6

Zdeněk Dvořák,

Barbora Vyhlídalová,

Petra Pečinková

et al.

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Unlocking the Potential: FKK6 as a Microbial Mimicry-Based Therapy for Chronic Inflammation-Associated Colorectal Cancer in a Murine Model

Sládeková,

Li,

DesMarais

et al. 2024

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Chronic intestinal inflammation significantly contributes to the development of colorectal cancer (CRC) and remains a pertinent clinical challenge, necessitating novel therapeutic approaches. Indole-based microbial metabolite mimics FKK6, which is a ligand and agonist of the pregnane X receptor (PXR), was recently demonstrated to have PXR-dependent anti-inflammatory and protective effects in a mouse model of dextran sodium sulfate (DSS)-induced acute colitis. Here, we examined the therapeutic potential of FKK6 in a mouse model (C57BL/6 FVB humanized PXR mice) of colitis-associated colon cancer (CAC) induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). FKK6 (2 mg/kg) displayed substantial anti-tumor activity, as revealed by reduced size and number of colon tumors, improved colon histopathology, and decreased expression of tumor markers (c-MYC, β-catenin, Ki-67, cyclin D) in the colon. In addition, we carried out the chronic toxicity (30 days) assessment of FKK6 (1 mg/kg and 2 mg/kg) in C57BL/6 mice. Histological examination of tissues, biochemical blood analyses, and immunohistochemical staining for Ki-67 and γ-H2AX showed no difference between FKK6-treated and control mice. Comparative metabolomic analyses in mice exposed for 5 days to DSS and administered with FKK6 (0.4 mg/kg) revealed no significant effects on several classes of metabolites in the mouse fecal metabolome. Ames and micronucleus tests showed no genotoxic and mutagenic potential of FKK6in vitro. In conclusion, anticancer effects of FKK6 in AOM/DSS-induced CAC, together with FKK6 safety data fromin vitrotests andin vivochronic toxicity study, and comparative metabolomic study, are supportive of the potential therapeutic use of FKK6 in the treatment of CAC.

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Unlocking the Potential: FKK6 as a Microbial Mimicry-Based Therapy for Chronic Inflammation-Associated Colorectal Cancer in a Murine Model

Sládeková,

Li,

DesMarais

et al. 2024

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In vitro safety signals for potential clinical development of the anti-inflammatory pregnane X receptor agonist FKK6

Cited by 1 publication

References 42 publications

Unlocking the Potential: FKK6 as a Microbial Mimicry-Based Therapy for Chronic Inflammation-Associated Colorectal Cancer in a Murine Model

Unlocking the Potential: FKK6 as a Microbial Mimicry-Based Therapy for Chronic Inflammation-Associated Colorectal Cancer in a Murine Model

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