Synthesis and Characterization of ULK1/2 Kinase Inhibitors that Inhibit Autophagy and Upregulate Expression of Major...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Autophagy inhibition is a potential cancer therapy, including for non-small cell lung cancer (NSCLC).
• Previous work identified SBP-7455, a dual inhibitor of unc-51-like kinase 1 (ULK1) and ULK2, effective in triple-negative breast cancer (TNBC).

Purpose of the Study:

• To design, synthesize, and characterize novel dual ULK1/2 inhibitors, SBP-5147 and SBP-7501.
• To evaluate the efficacy of these new inhibitors against NSCLC cells and their effects on autophagic flux.

Main Methods:

• Chemical synthesis and characterization of SBP-5147 and SBP-7501.
• Cytotoxicity assays against NSCLC cells.
• Assessment of autophagic flux inhibition in A549 cells.
• Pharmacokinetic evaluation of oral exposure.

Main Results:

• SBP-5147 and SBP-7501 demonstrate cytotoxicity against NSCLC cells.
• Both compounds inhibit autophagic flux in A549 cells.
• SBP-5147 and SBP-7501 exhibit superior oral exposure compared to SBP-7455 at lower doses.
• SBP-5147 increases major histocompatibility complex (MHC) class I expression in NSCLC cells, suggesting potential for overcoming immunotherapy resistance.

Conclusions:

• SBP-5147 and SBP-7501 are potent dual ULK1/2 inhibitors with potential as anti-cancer agents for NSCLC.
• These inhibitors may enhance immunotherapy by modulating MHC class I expression.
• ULK1/2 inhibitors represent a viable therapeutic strategy, alone or in combination with existing treatments, for cancer management.