Synthesis and Characterization of ULK1/2 Kinase Inhibitors That Inhibit Autophagy and Upregulate Expression of Major Histocompatibility Complex I for the Treatment of Non-Small Cell Lung Cancer

  • ACS Chem Biol. 2026 Mar 20;21(3):469-489. doi: 10.1021/acschembio.5c00711.
Fabiana Izidro A L Layng  1 ,  Huiyu Ren  1 ,  Nicole A Bakas  1 ,  Dhanya R Panickar  1 ,  Lester J Lambert  1 ,  Maria Celeridad  1 ,  Jiaqian Wu  1 ,  Laurent De Backer  1 ,  Preeti Chandrachud  1 ,  Allison S Limpert  1 ,  Mitchell Vamos  1 ,  Apirat Chaikuad  2  3 ,  Betsaida B Verdugo  1 ,  Patrick M Hagan  1 ,  Sonja N Brun  4 ,  Lutz Tautz  1 ,  Stefan Knapp  2  3 ,  Reuben J Shaw  4 ,  Guy S Salvesen  1 ,  Douglas J Sheffler  1 ,  Nicholas D P Cosford  1
Affiliations
  • 1. Center for Therapeutics Discovery, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, United States.
  • 2. Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Frankfurt 60438, Germany.
  • 3. Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Frankfurt 60438, Germany.
  • 4. Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, United States.
PMID: 41674365 DOI: 10.1021/acschembio.5c00711
Abstract

Autophagy inhibition represents a promising therapeutic approach for the management of various cancers including nonsmall cell lung Cancer (NSCLC). We previously reported SBP-7455, a dual inhibitor of unc-51-like kinase 1 (ULK1) and its homologue ULK2 and described its effects on triple-negative breast Cancer (TNBC) cells. Herein we report the design, synthesis, and characterization of SBP-5147 and SBP-7501, two new dual ULK1/2 inhibitors that are cytotoxic against NSCLC cells, inhibit autophagic flux in A549 cells, and present greater oral exposure than SBP-7455 at a lower dose. In addition, SBP-5147 effectively modulates Autophagy and increases the expression of major histocompatibility complex (MHC) class I in NSCLC cells, which may support the rationale for ULK1/2 inhibition as a strategy to overcome resistance to immunotherapy. Together these data support the use of ULK inhibitors as part of a Cancer treatment strategy, either as a single agent or in combination with current therapies.

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