Small molecule inhibition of the autophagy kinase ULK1 and identification of ULK1 substrates

By Daniel F Egan, M. Chun, Mitchell Vamos, Haixia Zou, Juan Rong, Chad J. Miller, H. Lou, Dhanya Raveendra-Panickar, chih‐cheng yang, Douglas J. Sheffler and 5 more. Molecules and Cells, 2015

658 citations recorded by the source corpus.

Summary Many tumors become addicted to autophagy for survival, suggesting inhibition of autophagy as a potential broadly-applicable cancer therapy. ULK1/Atg1 is the only serine/threonine kinase in the core autophagy pathway and thus represents an excellent drug target. Despite recent advances in the understanding of ULK1 activation by nutrient deprivation, how ULK1 promotes autophagy remains poorly understood. Here, we screened degenerate peptide libraries to deduce the optimal ULK1 substrate motif and discovered fifteen phosphorylation sites in core autophagy proteins that were verified as in vivo ULK1 targets. We utilized these ULK1 substrates to perform a cell-based screen to identify and characterize a potent ULK1 small molecule inhibitor. The compound SBI-0206965 is a highly selective ULK1 kinase inhibitor in vitro and suppressed ULK1-mediated phosphorylation events in cells, regulating autophagy and cell survival. SBI-0206965 greatly synergized with mTOR inhibitors to kill tumor cells, providing a strong rationale for their combined use in the clinic.

Subfields: Cell Biology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/58313233113b2172eec3b70dee4318e55e5de316

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. Alec C. Kimmelman
2. Chang S. Chan
3. J. Mehnert
4. Jae U. Jung
5. James H. Hurley
6. E. White

In Epidemiology

1. Alec C. Kimmelman
2. R. Amaravadi
3. Chang S. Chan
4. J. Mehnert
5. E. White
6. Jae U. Jung
7. James H. Hurley
8. Lindsey N. Young

In Molecular Biology

1. Alec C. Kimmelman
2. R. Amaravadi
3. Chang S. Chan
4. J. Mehnert
5. James H. Hurley
6. Lindsey N. Young
7. E. White
8. Guido Kroemer

Citations in the corpus

• Recent insights into the function of autophagy in cancer (2016, methodology): “Medicinal chemistry efforts were driven by structure activity relationship (SAR) data and led to the development of the lead compound SBI-0206965, with an IC50 of 108 nM for ULK1 kinase (Egan et al. 2015).”
• Regulated cell death (RCD) in cancer: key pathways and targeted therapies (2022, background): “SBI-0206965 is a highly selective ULK1 inhibitor (ULK1: IC50= 108 nM; ULK2: IC50= 711 nM), which could downregulate the ULK1-mediated phosphorylation to inhibit autophagy and survival of NSCLC cells.(211) Moreover, SBI-0206965 also inhibits the growth of neuroblastoma cell lines and promotes apoptos”
• Autophagy during viral infection — a double-edged sword (2018, background): “Nutrient starvation or rapamycin, which is an mToRC1 inhibitor, induces the formation of the active ulK1 complex, which ultimately phosphorylates and activates the Beclin 1-vPS34 complex 152, 153 .”
• Mechanisms of Autophagy Initiation (2017, background): “Super-resolution imaging of mammalian autophagy initiation sites shows that ATG9 vesicles and the ULK1 complex subunit ATG13 coalesce with ERGIC components COPI, COPII, and ERGIC53 (150) (Fig.”
• Autophagy, Metabolism, and Cancer (2015, positive): “Another potential target are the autophagy-initiating kinases ULK1 and 2, and newly developed inhibitors block autophagy in vitro (73, 74).”