生物活性

• 靶点

  ULK1 IC50:108nM

  ULK2 IC50:711nM

• 描述Autophagy is a central cellular mechanism for the elimination of damaged proteins, protein complexes, and organelles. Atg1, one of the components of autophagy, has two homologs, ULK1 and ULK2. ULK1 is required in autophagy initiation. SBI-0206965 is a highly selective ULK1 inhibitor with IC50 of 108 nM, about 7-fold selectivity over ULK2. SBI-0206965 suppresses autophagy induced by mTOR inhibition in A549 cells, and prevents ULK1-dependent cell survival in WT MEFs, which also induce cancer cell death. In TCGA KIRC cohorts, ULK1 expression was upregulated in 66.7% of frech ccRCC tissues. Knockdown of ULK1 and selective inhibition of ULK1 by SBI-0206965 under starvation conditions induced cell apoptosis in ccRCC cells. Nude mice inoculated subcutaneously with A498 cells were treated with 50 mg/kg SBI-0206965 and The A498 tumour growth rate was significantly suppressed without affecting of the renal structure in mice. In fve NSCLC cell lines (A549, H292, H460, H1299 and HCC827) and one normal human lung cell line (BEAS-2B), Ulk1 is associated with them. Treated with SBI-0206965, Inhibition of Ulk1 in A549, H460 and HCC827 suppressed cell viability in a dose-dependent manner and the ability to form clones was decreased. Furthermore, targeting Ulk1 using SBI-0206965 significantly impaired the viability of NSCLC cells after cisplatin treatment compared with cisplatin treatment without SBI-0206965. Besides, evaluation results in mRNA levels of Bcl2 and Bclxl under SBI0206965 treatment showed no downregulation, suggesting SBI0206965 treatment decreased apoptosis-related proteins.
• 作用机制SBI-0206965 occupies a pocket that partially overlaps the ATP active site in a type Iib inhibitor manner.

• 动物研究
  剂量	Mice: 5 mg/kg - 20 mg/kg[2] (i.p.), 50 mg/kg[3] (i.p.)
  给药途径	i.p.