WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H407159
CAS#: 1884220-36-3
Description: SBI0206965 is a potent and selective autophagy Kinase ULK1 Inhibitor. Many tumors become addicted to autophagy for survival, suggesting inhibition of autophagy as a potential broadly applicable cancer therapy. 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.
Hodoodo Cat#: H407159
Name: SBI0206965
CAS#: 1884220-36-3
Chemical Formula: C21H21BrN4O5
Exact Mass: 488.07
Molecular Weight: 489.330
Elemental Analysis: C, 51.55; H, 4.33; Br, 16.33; N, 11.45; O, 16.35
Synonym: SBI0206965; SBI-0206965; SBI 0206965.
IUPAC/Chemical Name: 2-((5-bromo-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)oxy)-N-methylbenzamide
InChi Key: NEXGBSJERNQRSV-UHFFFAOYSA-N
InChi Code: InChI=1S/C21H21BrN4O5/c1-23-19(27)13-7-5-6-8-15(13)31-20-14(22)11-24-21(26-20)25-12-9-16(28-2)18(30-4)17(10-12)29-3/h5-11H,1-4H3,(H,23,27)(H,24,25,26)
SMILES Code: O=C(NC)C1=CC=CC=C1OC2=NC(NC3=CC(OC)=C(OC)C(OC)=C3)=NC=C2Br
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | SBI-0206965 is a cell permeable autophagy kinase ULK1 inhibitor with IC50s of 108 nM for ULK1 kinase and 711 nM for the highly related kinase ULK2. |
| In vitro activity: | In this study, SBI-0206965 has limited additive effect on the cytotoxicity of either mTOR inhibitors (INK128 and Torin1) or conventional chemotherapies (doxorubicin and topotecan) in neuroblastoma cell lines. However, SBI-0206965 was observed to reduce AKT(S473) phosphorylation, a predictor of poor outcome in neuroblastoma, indicating that SBI-0206965 reduces key oncogenic pathways in neuroblastoma. Moreover, the influence of SBI-0206965 on AKT activity may explain why this study failed to see synergistic effects from co-treatments of SBI-0206965 and mTOR inhibitors. In support of this, expression of dnULK1 did not reduce AKT(S473) phosphorylation and sensitized SK-N-AS cells to mTORC1/2 inhibition, resulting in levels of apoptosis similar to that of SBI-0206965 treatment. Reference: Mol Cancer Ther. 2018 Nov; 17(11): 2365–2376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215526/ |
| In vivo activity: | To validate findings after transduction with AAV.ULK1.DN, this study performed acute (30 min) pharmacological ULK1 inhibition using SBI (SBI0206965) in rat cortical neurons and studied the effects on the mTOR pathway. Consistently, treatment with SBI did not alter total mTOR expression but significantly increased the levels of p-mTOR compared with control (Fig. 6i, j). The total levels of S6 and 4E-BP1 were not significantly regulated (Fig. 6k, m), while the analysis of p-S6 and p-4E-BP1 showed nonsignificant trends to higher levels after SBI administration (Fig. 6l, n). The expression of AMPKα remained unchanged (Fig. 6o). Surprisingly, SBI led to increased p-AMPK levels in rapamycin-treated conditions (Fig. 6p), arguing against a crucial role of reduced AMPK activity for increased mTOR activity through ULK1 inhibition, at least in this acute paradigm. Taken together, these data suggest that increased translation following ULK1 inhibition is mediated through an mTOR-dependent mechanism, representing an additional molecular mediator of its degeneration-attenuating effect. Reference: Cell Death Differ. 2020 Oct; 27(10): 2810–2827. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493890/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 75.7 | 154.64 | |
| DMSO:PBS (pH 7.2) (1:1) | 0.5 | 1.02 | |
| DMF | 30.0 | 61.31 | |
| Ethanol | 10.5 | 21.46 |
The following data is based on the product molecular weight 489.33 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Dower CM, Bhat N, Gebru MT, Chen L, Wills CA, Miller BA, Wang HG. Targeted Inhibition of ULK1 Promotes Apoptosis and Suppresses Tumor Growth and Metastasis in Neuroblastoma. Mol Cancer Ther. 2018 Nov;17(11):2365-2376. doi: 10.1158/1535-7163.MCT-18-0176. Epub 2018 Aug 30. PMID: 30166400; PMCID: PMC6215526. 2. Lu J, Zhu L, Zheng LP, Cui Q, Zhu HH, Zhao H, Shen ZJ, Dong HY, Chen SS, Wu WZ, Tan JM. Overexpression of ULK1 Represents a Potential Diagnostic Marker for Clear Cell Renal Carcinoma and the Antitumor Effects of SBI-0206965. EBioMedicine. 2018 Aug;34:85-93. doi: 10.1016/j.ebiom.2018.07.034. Epub 2018 Aug 2. PMID: 30078736; PMCID: PMC6116477. 3. Vahsen BF, Ribas VT, Sundermeyer J, Boecker A, Dambeck V, Lenz C, Shomroni O, Caldi Gomes L, Tatenhorst L, Barski E, Roser AE, Michel U, Urlaub H, Salinas G, Bähr M, Koch JC, Lingor P. Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing. Cell Death Differ. 2020 Oct;27(10):2810-2827. doi: 10.1038/s41418-020-0543-y. Epub 2020 Apr 27. PMID: 32341448; PMCID: PMC7493890. 4. Knudsen JR, Madsen AB, Persson KW, Henríquez-Olguín C, Li Z, Jensen TE. The ULK1/2 and AMPK Inhibitor SBI-0206965 Blocks AICAR and Insulin-Stimulated Glucose Transport. Int J Mol Sci. 2020 Mar 28;21(7):2344. doi: 10.3390/ijms21072344. PMID: 32231045; PMCID: PMC7177789. |
| In vitro protocol: | 1. Dower CM, Bhat N, Gebru MT, Chen L, Wills CA, Miller BA, Wang HG. Targeted Inhibition of ULK1 Promotes Apoptosis and Suppresses Tumor Growth and Metastasis in Neuroblastoma. Mol Cancer Ther. 2018 Nov;17(11):2365-2376. doi: 10.1158/1535-7163.MCT-18-0176. Epub 2018 Aug 30. PMID: 30166400; PMCID: PMC6215526. 2. Lu J, Zhu L, Zheng LP, Cui Q, Zhu HH, Zhao H, Shen ZJ, Dong HY, Chen SS, Wu WZ, Tan JM. Overexpression of ULK1 Represents a Potential Diagnostic Marker for Clear Cell Renal Carcinoma and the Antitumor Effects of SBI-0206965. EBioMedicine. 2018 Aug;34:85-93. doi: 10.1016/j.ebiom.2018.07.034. Epub 2018 Aug 2. PMID: 30078736; PMCID: PMC6116477. |
| In vivo protocol: | 1. Vahsen BF, Ribas VT, Sundermeyer J, Boecker A, Dambeck V, Lenz C, Shomroni O, Caldi Gomes L, Tatenhorst L, Barski E, Roser AE, Michel U, Urlaub H, Salinas G, Bähr M, Koch JC, Lingor P. Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing. Cell Death Differ. 2020 Oct;27(10):2810-2827. doi: 10.1038/s41418-020-0543-y. Epub 2020 Apr 27. PMID: 32341448; PMCID: PMC7493890. 2. Knudsen JR, Madsen AB, Persson KW, Henríquez-Olguín C, Li Z, Jensen TE. The ULK1/2 and AMPK Inhibitor SBI-0206965 Blocks AICAR and Insulin-Stimulated Glucose Transport. Int J Mol Sci. 2020 Mar 28;21(7):2344. doi: 10.3390/ijms21072344. PMID: 32231045; PMCID: PMC7177789. |
1: Dual Inhibition of ULK1 and mTOR Enhances Tumor Cell Apoptosis. Cancer Discov.
2015 Sep;5(9):OF5. doi: 10.1158/2159-8290.CD-RW2015-127. Epub 2015 Jul 9. PubMed
PMID: 26159593.
2: Egan DF, Chun MG, Vamos M, Zou H, Rong J, Miller CJ, Lou HJ,
Raveendra-Panickar D, Yang CC, Sheffler DJ, Teriete P, Asara JM, Turk BE, Cosford
ND, Shaw RJ. Small Molecule Inhibition of the Autophagy Kinase ULK1 and
Identification of ULK1 Substrates. Mol Cell. 2015 Jul 16;59(2):285-97. doi:
10.1016/j.molcel.2015.05.031. Epub 2015 Jun 25. PubMed PMID: 26118643; PubMed
Central PMCID: PMC4530630.
