产品号 #100-0269_C
ULK1和ULK2激酶抑制剂
总览
SBI-0206965是自噬启动激酶ULK1和ULK2的抑制剂(IC₅₀分别为108 nM和711 nM；Egan等人)。SBI-0206965也是腺苷酸活化蛋白激酶（AMPK）的强效抑制剂，AMPK是自噬的正调节因子（Dite等人）。
肿瘤研究
·与mTOR抑制协同作用，诱导肿瘤细胞凋亡和细胞死亡（Egan等人）。
·抑制mTOR抑制剂诱导的自噬（Egan等人）。
·通过抑制AMPK和ULK1来抑制肿瘤细胞中促存活的自噬反应（Dite等人）。
别名
Not applicable
细胞类型
癌细胞及细胞系
研究领域
自噬，癌症
CAS 编号
1884220-36-3
化学式
C₂₁H₂₁BrN₄O₅
分子量
489.3 克/摩尔
纯度
≥98%
通路
mTOR
靶点
ULK1，ULK2
Protocols and Documentation
Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.
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.
更多信息
| Molecular Weight | 489.3 g/mol |
|---|---|
| Alternative Names | Not applicable |
| Cas Number | 1884220-36-3 |
| Chemical Formula | C₂₁H₂₁BrN₄O₅ |
| Purity | ≥ 98% |
| Target | ULK1, ULK2 |
| Pathway | mTOR |
PRODUCTS ARE FOR RESEARCH USE ONLY AND NOT INTENDED FOR HUMAN OR ANIMAL DIAGNOSTIC OR THERAPEUTIC USES UNLESS OTHERWISE STATED.
