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

Fabiana Izidro A L Layng1, Huiyu Ren1, Nicole A Bakas1

  • 1Center for Therapeutics Discovery, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States.

ACS Chemical Biology
|February 12, 2026
PubMed

Insights

New dual ULK1/2 inhibitors, SBP-5147 and SBP-7501, show promise for treating non-small cell lung cancer (NSCLC). These compounds are cytotoxic, inhibit autophagy, and offer improved oral exposure, potentially enhancing immunotherapy responses.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Autophagy inhibition is a potential cancer therapy, particularly for non-small cell lung cancer (NSCLC).
  • Previous research identified SBP-7455 as a dual inhibitor of unc-51-like kinase 1 (ULK1) and ULK2, showing effects 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 compounds against NSCLC cells and their effects on autophagic flux.
  • To assess the pharmacokinetic properties and potential immunomodulatory effects of the new inhibitors.

Main Methods:

  • Chemical synthesis and characterization of SBP-5147 and SBP-7501.
  • Cytotoxicity assays on NSCLC cell lines.
  • Assessment of autophagic flux inhibition in A549 cells.
  • Pharmacokinetic studies to determine oral exposure.
  • Analysis of major histocompatibility complex (MHC) class I expression.

Main Results:

  • SBP-5147 and SBP-7501 demonstrated cytotoxicity against NSCLC cells.
  • Both compounds inhibited autophagic flux in A549 cells.
  • SBP-5147 and SBP-7501 exhibited greater oral exposure than SBP-7455 at lower doses.
  • SBP-5147 modulated autophagy and increased MHC class I expression in NSCLC cells.

Conclusions:

  • SBP-5147 and SBP-7501 are effective dual ULK1/2 inhibitors with potential for NSCLC treatment.
  • These compounds offer improved pharmacokinetic profiles compared to SBP-7455.
  • ULK1/2 inhibition may enhance immunotherapy by increasing MHC class I expression, suggesting a role in overcoming resistance.
  • ULK inhibitors represent a viable therapeutic strategy, alone or in combination therapies for cancer.

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