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

Layng, F. I. A. L.; Ren, H.; Bakas, N. A.; Panickar, D. R.; Lambert, L. J.; Celeridad, M.; Wu, J.; De Backer, L.; Chandrachud, P.; Limpert, A. S.; Vamos, M.; Chaikuad, A.; Verdugo, B. B.; Hagan, P. M.; Brun, S. N.; Tautz, L.; Knapp, S.; Shaw, R. J.; Salvesen, G. S.; Sheffler, D. J.; Cosford, N. D. P.

doi:10.1101/2025.09.05.674519

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bioRxiv · 10.1101/2025.09.05.674519

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

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Abstract

Autophagy inhibition represents a promising therapeutic approach for the management of various cancers including non-small 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, both as a single agent as well as in combination with current therapies.

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Layng, F. I. A. L., Ren, H., Bakas, N. A., Panickar, D. R., Lambert, L. J., Celeridad, M., Wu, J., De Backer, L., Chandrachud, P., Limpert, A. S., Vamos, M., Chaikuad, A., Verdugo, B. B., Hagan, P. M., Brun, S. N., Tautz, L., Knapp, S., Shaw, R. J., Salvesen, G. S., Sheffler, D. J., Cosford, N. D. P.. 2025-09-10. 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. https://doi.org/10.1101/2025.09.05.674519

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