SBI-0206965
SBI-0206965 is a novel inhibitor of the autophagy-initiating kinase ULK1.
ULK1 (Unc-51 like Autophagy Activating Kinase 1) is a serine/threonine-protein kinase involved in autophagy in starvation. It is an AMPK regulator, a downstream effector and negative regulator of mTORC1. It also plays a role in neuronal differentiation. [1]
In A549 cells, 5 mM SBI-0206965 strongly suppresses the AZD8055 induced autophagy effect. In SBI-0206965 treated MEFs, after 18 hours of amino acid deprivation, 42% of 6965-treated cells shows 7-AAD and AnnexinV (end stage apoptosis). SBI-02066965 also promotes apoptosis
in the nutrient-starved state in human U87MG glioblastoma cells and in murine lung carcinoma cells. Moreover, 5 mM SBI-0206965 triggers apoptosis in 23% of cells when combined with AZD8055 versus 10% of cells in the absence of AZD8055 and 7% of cells treated with AZD8055
alone. Similar to AZD8055, both rapamycin and INK128 exhibits a mild apoptotic response on their own in A549 cells but significantly enhances this apoptotic response when combined with SBI-0206965. [1]
Reference:
[1] Egan DF, Chun MG, Vamos M et al. Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates. Mol Cell. 2015 Jul 16; 59 (2): 285-97.
- 1. Gangyin Zhao, Gabriel Forn-Cuní, et al. "Simultaneous targeting of AMPK and mTOR is a novel therapeutic strategy against prostate cancer" bioRxiv. August 16, 2023.
- 2. Jonas Sundermeyer. "Effekte einer pharmakologischen Inhibition der ULK1-Kinase auf die akute axonalen Degeneration in vivo." G?ttingen 2022.
- 3. Mathieu Paquette, Leeanna El-Houjeiri, et al. "AMPK-dependent phosphorylation is required for transcriptional activation of TFEB and TFE3." Autophagy. 2021 Dec;17(12):3957-3975. PMID: 33734022
- 4. Yoon-Jin Kim, Qingyao Kong, et al. "An autophagy-related protein Becn2 regulates cocaine reward behaviors in the dopaminergic system." Sci Adv. 2021 Feb 19;7(8):eabc8310. PMID: 33608268
- 5. Vahsen BF, Ribas VT, et al. "Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing." Cell Death Differ. 2020;10.1038/s41418-020-0543-y. PMID: 32341448
- 6. Dite TA, Langendorf CG, et al. "AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965." J Biol Chem. 2018 Jun 8;293(23):8874-8885. PMID: 29695504
- 7. Dite TA, Ling NXY, et al. "The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs." Nat Commun. 2017 Sep 18;8(1):571. PMID: 28924239
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 489.32 |
| Cas No. | 1884220-36-3 |
| Formula | C21H21BrN4O5 |
| Solubility | ≥24.47 mg/mL in DMSO; insoluble in H2O; ≥5 mg/mL in EtOH with ultrasonic |
| Chemical Name | (Z)-2-((5-bromo-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)oxy)-N-methylbenzimidic acid |
| SDF | Download SDF |
| Canonical SMILES | C/N=C(O)/C1=CC=CC=C1OC2=NC(NC3=CC(OC)=C(OC)C(OC)=C3)=NC=C2Br |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Cell experiment [1]: | |
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Cell lines |
HEK293T cells transfected with WT or KI Myc-tagged ULK1 and WT Vps34 |
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Preparation method |
The solubility of this compound in DMSO is >24.5 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37°C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20°C for several months. |
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Reacting condition |
1, 10 and 50 μM; 1 hr |
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Applications |
In HEK293T cells transfected with WT or KI Myc-tagged ULK1 and WT Vps34, SBI-0206965 inhibited Ser249 phosphorylation of overexpressed Vps34 at the dose of ~5 μM. In HEK293T cells, it was found that SBI-0206965 also inhibited the phosphorylation of Beclin1 Ser15 to comparable extents. |
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References: [1] Egan DF, Chun MG, Vamos M et al. Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates. Mol Cell. 2015 Jul 16; 59 (2): 285-97. |
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