SBI-0206965 is an inhibitor of the autophagy initiator kinases ULK1 and ULK2 (IC₅₀ = 108 nM and 711 nM, respectively; Egan et al.). SBI-0206965 is also a potent inhibitor of AMP-activated protein kinase (AMPK), a positive regulator of autophagy (Dite et al.).
CANCER RESEARCH
· Synergizes with mTOR inhibition to induce apoptosis and cell death in tumor cells (Egan et al.).
· Suppresses autophagy induced by mTOR inhibition (Egan et al.).
· Suppresses prosurvival autophagic responses in tumor cells through AMPK and ULK1 inhibition (Dite et al.).
CANCER RESEARCH
· Synergizes with mTOR inhibition to induce apoptosis and cell death in tumor cells (Egan et al.).
· Suppresses autophagy induced by mTOR inhibition (Egan et al.).
· Suppresses prosurvival autophagic responses in tumor cells through AMPK and ULK1 inhibition (Dite et al.).
未找到
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
未找到
Resources and Publications
Publications (2)
AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965. The Journal of biological chemistry 2018
Abstract
Inhibition of the metabolic regulator AMP-activated protein kinase (AMPK) is increasingly being investigated for its therapeutic potential in diseases where AMPK hyperactivity results in poor prognoses, as in established cancers and neurodegeneration. However, AMPK-inhibitory tool compounds are largely limited to compound C, which has a poor selectivity profile. Here we identify the pyrimidine derivative SBI-0206965 as a direct AMPK inhibitor. SBI-0206965 inhibits AMPK with 40-fold greater potency and markedly lower kinase promiscuity than compound C and inhibits cellular AMPK signaling. Biochemical characterization reveals that SBI-0206965 is a mixed-type inhibitor. A co-crystal structure of the AMPK kinase domain/SBI-0206965 complex shows that the drug occupies a pocket that partially overlaps the ATP active site in a type IIb inhibitor manner. SBI-0206965 has utility as a tool compound for investigating physiological roles for AMPK and provides fresh impetus to small-molecule AMPK inhibitor therapeutic development.
Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates. Molecular cell 2015 jul
Abstract
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.
PRODUCTS ARE FOR RESEARCH USE ONLY AND NOT INTENDED FOR HUMAN OR ANIMAL DIAGNOSTIC OR THERAPEUTIC USES UNLESS OTHERWISE STATED.
