Identification of a Dual Autophagy and REV-ERB Inhibitor with in Vivo Anticancer Efficacy

Area of Science:

• Molecular Biology
• Pharmacology
• Oncology

Background:

• Autophagy is a key target for cancer therapy, with chloroquine (CQ) and hydroxychloroquine (HCQ) being FDA-approved inhibitors.
• Limitations of current autophagy inhibitors include high dosage and long-term administration requirements.
• REV-ERB, a nuclear receptor involved in circadian rhythm and metabolism, has emerged as a potential modulator of cancer cell death.

Purpose of the Study:

• To investigate the potential of inhibiting REV-ERB to enhance autophagy inhibitor efficacy in cancer.
• To identify novel dual inhibitors targeting both autophagy and REV-ERB with improved anticancer properties.
• To optimize lead compounds and evaluate their efficacy as single-agent anticancer therapies.

Main Methods:

• Inhibition of REV-ERB was explored to potentiate CQ-mediated cancer cell death.
• A class of dual autophagy and REV-ERB inhibitors was synthesized and evaluated for in vitro anticancer activity.
• Lead optimization led to compound 24, which was further assessed for potency, drug-like properties, and in vivo efficacy in a melanoma xenograft model.

Main Results:

• Inhibition of REV-ERB significantly enhanced CQ-induced cancer cell death.
• Dual autophagy and REV-ERB inhibitors demonstrated superior in vitro anticancer activity compared to CQ alone.
• Compound 24 exhibited improved autophagy inhibition, enhanced cancer cell toxicity, favorable drug-like properties, and significant efficacy in a preclinical melanoma model.

Conclusions:

• Dual inhibition of autophagy and REV-ERB represents a potent anticancer strategy.
• Compound 24 is a promising single-agent therapeutic candidate for melanoma and potentially other cancers.
• Targeting REV-ERB offers a novel approach to overcome limitations of current autophagy-based cancer treatments.