Curaxins: anticancer compounds that simultaneously suppress NF-κB and activate p53 by targeting FACT

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Cancer treatment necessitates targeting multiple dysregulated pathways, including p53 activation and nuclear factor κB (NF-κB) inhibition.
• Existing therapies often face challenges with genotoxicity and limited efficacy against diverse tumor types.

Purpose of the Study:

• To identify and characterize small molecules (curaxins) that simultaneously modulate p53 and NF-κB pathways.
• To elucidate the mechanism of action of curaxins, focusing on their interaction with the FACT complex.
• To evaluate the anticancer efficacy and safety profile of curaxins in preclinical models.

Main Methods:

• Isolation and structural optimization of curaxin compounds.
• In vitro and in vivo assays to assess p53 activation, NF-κB inhibition, and anticancer activity against human tumor xenografts.
• Chromatin immunoprecipitation and biochemical assays to investigate the interaction of curaxins with the FACT complex and downstream signaling.

Main Results:

• Curaxins effectively activate p53 and inhibit NF-κB signaling without inducing genotoxicity.
• Curaxins demonstrate broad-spectrum anticancer activity against various human tumor xenografts in mice.
• The mechanism involves "chromatin trapping" of the FACT complex, leading to p53 Ser(392) phosphorylation and inhibition of NF-κB transcription.

Conclusions:

• FACT is identified as a novel therapeutic target for simultaneous modulation of p53 and NF-κB pathways.
• Curaxins represent a promising class of anticancer agents with a unique mechanism of action and favorable safety profile.
• Targeting FACT offers a potential strategy for developing effective and safe cancer therapeutics with reduced DNA damage.