A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

Area of Science:

• Oncology
• Biochemistry
• Pharmacology

Background:

• Lysosomes play a dual role in cancer metabolism, supporting both catabolism (autophagy, macropinocytosis) and anabolism.
• Existing lysosomal inhibitors like chloroquine do not inhibit mTOR signaling, and their molecular targets remain unknown.
• Antimalarial compounds offer potential but require refinement for targeted cancer therapy.

Purpose of the Study:

• To identify novel dimeric antimalarials with potent anticancer activity.
• To elucidate the molecular target and mechanism of action of these new compounds.
• To evaluate their efficacy in preclinical cancer models and assess combination potential.

Main Methods:

• Screening of novel dimeric antimalarials, including dimeric quinacrines (DQ).
• Chemical modification (central nitrogen methylation) to enhance lysosomal localization and potency.
• In situ photoaffinity pulldown to identify the molecular target.
• Inhibition assays for mTOR signaling and lysosomal catabolism.
• In vivo studies in melanoma, pancreatic, and colorectal cancer mouse models.

Main Results:

• Dimeric quinacrines (DQ) were identified as potent anticancer compounds concurrently inhibiting mTOR and autophagy.
• Central nitrogen methylation of the DQ linker improved lysosomal targeting and efficacy.
• Palmitoyl-protein thioesterase 1 (PPT1) was identified as the molecular target of DQ661.
• PPT1 inhibition led to rapid accumulation of palmitoylated proteins, impairing both mTOR and lysosomal catabolism.
• DQ661 demonstrated efficacy in inhibiting tumor growth in multiple cancer models and was safe in combination therapy.

Conclusions:

• Lysosome-directed PPT1 inhibitors represent a novel therapeutic strategy for cancer.
• Targeting PPT1 concurrently inhibits mTORC1 signaling and lysosomal catabolism.
• Dimeric compounds with enhanced lysosomal specificity offer a new class of targeted cancer therapies.
• PPT1 inhibition provides a distinct mechanism for blocking mTOR signaling, complementary to existing inhibitors.