Reference Detail

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 Molecular cell
Vol 59
Issue 2
Date 2015 Jul 16
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).
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
Unknown unknown lung non-small cell carcinoma not applicable AZD8055 + SBI-0206965 Preclinical - Cell culture Actionable In a preclinical study, the addition of SBI-0206965 to treatment with AZD8055 resulted in increased apoptosis in a non-small cell lung cancer cell line in culture (PMID: 26118643). 26118643
Unknown unknown lung non-small cell carcinoma not applicable Sapanisertib + SBI-0206965 Preclinical - Cell culture Actionable In a preclinical study, the addition of SBI-0206965 to treatment with Sapanisertib (MLN0128) resulted in increased apoptosis in a non-small cell lung cancer cell line in culture (PMID: 26118643). 26118643
Unknown unknown lung non-small cell carcinoma not applicable SBI-0206965 + Sirolimus Preclinical - Cell culture Actionable In a preclinical study, the addition of SBI-0206965 to treatment with Rapamune (sirolimus) resulted in increased apoptosis in a non-small cell lung cancer cell line in culture (PMID: 26118643). 26118643