2. Academic Validation
  3. 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

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

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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