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

Article

作者: Brun, Sonja N. ; Knapp, Stefan ; Cosford, Nicholas D. P. ; Limpert, Allison S. ; Verdugo, Betsaida B. ; Wu, Jiaqian ; Chandrachud, Preeti ; Lambert, Lester J. ; Panickar, Dhanya R. ; De Backer, Laurent ; Sheffler, Douglas J. ; Shaw, Reuben J. ; Salvesen, Guy S. ; Celeridad, Maria ; Hagan, Patrick M. ; Ren, Huiyu ; Layng, Fabiana Izidro A. L. ; Bakas, Nicole A. ; Vamos, Mitchell ; Chaikuad, Apirat ; Tautz, Lutz

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.

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

Article

作者: Lester J. Lambert ; Jiaqian Wu ; Stefan Knapp ; Dhanya R. Panickar ; Sonja N. Brun ; Lutz Tautz ; Allison S. Limpert ; Betsaida B. Verdugo ; Guy S. Salvesen ; Nicholas D. P. Cosford ; Nicole A. Bakas ; Mitchell Vamos ; Fabiana Izidro A. L. Layng ; Laurent De Backer ; Douglas J. Sheffler ; Huiyu Ren ; Apirat Chaikuad ; Maria Celeridad ; Patrick M. Hagan ; Preeti Chandrachud ; Reuben J. Shaw

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.

100 项与 SBP-7501 相关的药物交易

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