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Ref Type Journal Article
PMID (26118643)
Authors Egan DF, Chun MG, Vamos M, Zou H, Rong J, Miller CJ, Lou HJ, Raveendra-Panickar D, Yang CC, Sheffler DJ, Teriete P, Asara JM, Turk BE, Cosford ND, Shaw RJ
Title Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates.
Journal Vol Issue Date Pages Journal Short Title
Molecular cell 59 2 2015 Jul 16 285-97 Mol Cell
URL
Abstract Text 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 15 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 mechanistic target of rapamycin (mTOR) inhibitors to kill tumor cells, providing a strong rationale for their combined use in the clinic.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SBI-0206965 SBI-0206965 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SBI-0206965 SBI-0206965 is a small molecule that selectively inhibits ULK1, resulting in decreased phosphorylation of ULK1 targets, and potentially leading to increased tumor cell death in combination with mTOR inhibitors (PMID: 26118643, PMID: 30166400, PMID: 32393312).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References