Description
ULK1 is a serine/threonine kinase that acts upstream of phosphatidylinositol 3-kinase (PI3K) to regulate the formation of autophagophores, the precursors of autophagosomes, in response to nutrient deprivation. It is activated by phosphorylation by AMPK and, in turn, phosphorylates and inhibits AMPK. SBI-0206965 is an inhibitor of ULK1 (IC
50 = 108 nM) that is less effective against ULK2 (IC
50 = 711 nM). It is selective for ULK1 and ULK2 over a panel of 456 additional kinases, showing activity against a few kinases
in vitro but not in cells. SBI-0206965 suppresses autophagy induced by mTOR inhibition
via AZD 8055 . It also blocks ULK1-dependent cell survival following nutrient deprivation.
Uses
SBI-0206965 is an inhibitor of ULK1. It also blocks ULK1-dependent cell survival following nutrient deprivation. ULK1 is a serine/threonine kinase that acts upstream of phosphatidylinositol 3-kinase (PI3K) to regulate the formation of autophagophores, the precursors of autophagosomes, in response to nutrient deprivation.
Biochem/physiol Actions
Since most of the tumor cells survive on autophagy mechanism, inhibition of autophagy inducers Unc-51 (serine/threonine-protein kinase)-like autophagy activating kinase (ULK1 and ULK2) might be useful in cancer therapy.
in vivo
SBI-0206965 (50mg/kg; i.p.; once every 3 days for 37 days) inhibites tumour growth and induces apoptosis in A498 xenograft tumours[1].
| Animal Model: | Six-week-old male BALB/c nude mice (A498 xenograft tumours)[1] |
| Dosage: | 50mg/kg |
| Administration: | Intraperitoneal injection; once every three days for 37 days |
| Result: | Significantly suppressed tumour growth. |
IC 50
ULK1: 108 nM (IC
50); ULK2: 711 nM (IC
50)
Background
SBI-0206965 is a potent, selective and cell permeable inhibitor of the autophagy-promoting serine/threonine kinase ULK1. ULK1 is an essential protein for induction of autophagy by nutrient starvation and mTOR inhibition. ULK1 is recripocally regulated by multple phosphorylation sites via AMPK and mTOR, such that ULK1 is activated by AMPK and inhibited by mTOR. By in vitro kinase assays, SBI-0206965 inhibits ULK1 with an IC50 of 108 nM and to a lesser extent ULK2 with an IC50 of 711 nM. In a panel of 456 kinases, when tested at 10 μM, SBI-0206965 showed remarkable selectivity and only inhibited 10 kinases, including ULK1 and ULK2. Other kinase that were inhibited included FAK, FLT3, Src, and Jak3. Only FLT3 and FAK had an IC50 similar to ULK1 when tested in in vitro kinase assays. SBI-020695 inhibits survival following nutrient deprivation. Furthermore, SBI-0206965 inhibits autophagy induced by mTOR inhibition and converts the cytostatic response to mTOR inhibition to a cytotoxic apoptotic response.
References
[1] DANIEL F EGAN. Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates.[J]. Molecular Cell, 2015: 285-297. DOI:
10.1016/j.molcel.2015.05.031
