Drain the lysosome: Development of the novel orally available autophagy inhibitor ROC-325

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Macroautophagy (autophagy) plays a critical role in cancer development and treatment resistance.
• Currently, limited FDA-approved drugs effectively target the autophagy pathway.
• Lysosomal-mediated autophagy is a key process in cellular homeostasis and disease.

Purpose of the Study:

• To develop and characterize ROC-325, a novel, orally available inhibitor of lysosomal autophagy.
• To evaluate the efficacy and safety of ROC-325 in preclinical models of cancer.
• To compare ROC-325's performance against hydroxychloroquine, a known autophagy inhibitor.

Main Methods:

• Medicinal chemistry strategies were employed to design and synthesize ROC-325.
• In vitro and in vivo studies were conducted using preclinical models, specifically renal cell carcinoma.
• Assays were performed to assess hallmark features of lysosomal autophagy inhibition, drug tolerability, and anticancer activity.

Main Results:

• ROC-325 demonstrated hallmark features of lysosomal autophagy inhibition in preclinical models.
• The drug was well-tolerated in these studies.
• ROC-325 exhibited superior autophagy inhibition and anticancer efficacy compared to hydroxychloroquine.

Conclusions:

• ROC-325 is a promising novel inhibitor of lysosomal autophagy with significant preclinical anticancer activity.
• The drug's favorable tolerability and superior efficacy warrant further clinical investigation.
• ROC-325 holds potential for treating autophagy-dependent malignancies and other diseases linked to aberrant autophagy.