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|Ref Type||Journal Article|
|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.|
|Date||2015 Jul 16|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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).|
|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|
|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|
|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|