A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Drug resistance and secondary malignancies limit chemotherapy effectiveness.
• Mutagenic translesion synthesis (TLS) promotes chemoresistance and treatment-induced mutations.
• Targeting TLS is a promising strategy to improve chemotherapeutics, but specific inhibitors are challenging to develop.

Purpose of the Study:

• To discover and characterize a novel small-molecule inhibitor targeting mutagenic TLS.
• To evaluate the efficacy of the inhibitor in preclinical cancer models.

Main Methods:

• Discovery of JH-RE-06, a small-molecule inhibitor of mutagenic TLS.
• Investigation of JH-RE-06's mechanism of action, focusing on REV1 and POL ζ interaction.
• Assessment of JH-RE-06's ability to inhibit mutagenic TLS in vitro.
• Evaluation of JH-RE-06's effect on cisplatin-induced toxicity in cell lines.
• Testing the efficacy of JH-RE-06 combined with cisplatin in a xenograft human melanoma mouse model.

Main Results:

• JH-RE-06 disrupts mutagenic TLS by preventing the recruitment of mutagenic POL ζ.
• The inhibitor binds to REV1, inducing dimerization and blocking the REV1-REV7 interaction.
• JH-RE-06 inhibits mutagenic TLS and potentiates cisplatin-induced toxicity in human and mouse cell lines.
• Combined administration of JH-RE-06 and cisplatin suppressed xenograft melanoma growth in mice.

Conclusions:

• JH-RE-06 is a potent inhibitor of mutagenic TLS with in vivo efficacy.
• This study establishes a framework for developing TLS inhibitors as novel chemotherapy adjuvants.
• Targeting TLS offers a promising strategy to overcome chemoresistance and enhance cancer treatment outcomes.