WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205710
CAS#: 1025065-69-3
Description: SGI-1776 is a small-molecule pan-Pim protein kinase inhibitor with potential antineoplastic activity. Pim kinase inhibitor SGI-1776 binds to and inhibits the activities of Pim-1, -2 and -3, serine-threonine kinases, which may result in the interruption of the G1/S phase cell cycle transition, the expression of pro-apoptotic Bcl2 proteins and tumor cell apoptosis. PIM kinases play key roles in cell cycle progression and apoptosis inhibition and may be overexpressed in various malignancies.
MedKoo Cat#: 205710
Name: SGI-1776
CAS#: 1025065-69-3
Chemical Formula: C20H22F3N5O
Exact Mass: 405.17764
Molecular Weight: 405.42
Elemental Analysis: C, 59.25; H, 5.47; F, 14.06; N, 17.27; O, 3.95
Synonym: SGI1776; SGI-1776; SGI 1776.
IUPAC/Chemical Name: N-((1-methylpiperidin-4-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine.
InChi Key: SXLKQFDJPFXMGV-UHFFFAOYSA-N
InChi Code: InChI=1S/C20H22F3N5O/c1-27-10-8-14(9-11-27)12-24-18-6-7-19-25-13-17(28(19)26-18)15-2-4-16(5-3-15)29-20(21,22)23/h2-7,13-14H,8-12H2,1H3,(H,24,26)
SMILES Code: FC(F)(F)OC1=CC=C(C2=CN=C3C=CC(NCC4CCN(C)CC4)=NN32)C=C1
Appearance: white 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
| Biological target: | SGI-1776 is an inhibitor of Pim kinases, with IC50s of 7 nM, 363 nM, and 69 nM for Pim-1, -2 and -3, respectively. |
| In vitro activity: | As shown in Fig. 1H and I, SGI-1776 induced a significant dose-dependent increase in apoptotic death in TPC-1 and BCPAP cells. Furthermore, a wound-healing assay was used to evaluate the effect of SGI-1776 on cell migration. As shown in Fig. 1J, the wound-healing rates of both PTC cell lines at each time point markedly decreased after treatment with 2.5 μM or 5 μM SGI-1776 for 24, 48, or 72 h compared with those in the control group. Besides, the inhibitory effect of SGI-1776 on the migration of BRAF-positive BCPAP cells was more pronounced than that of RET/PTC-positive TPC-1 cells. These data indicated that SGI-1776 could effectively inhibit proliferation, colony formation, and migration and promote apoptosis of BCPAP and TPC-1 cells. Reference: Mol Cell Endocrinol. 2021 Mar 1;523:111144. https://pubmed.ncbi.nlm.nih.gov/33383107/ |
| In vivo activity: | Potent and sustained antitumor activity was seen in MV-4-11 xenografts with oral administration of SGI-1776 (Figure 5A), with tumors in the 75 mg/kg and 200 mg/kg treatment groups disappearing or became almost impalpable within 1 week after treatment. On day 22 of the experiment, 8 of 9 mice treated with 75 mg/kg SGI-1776 and all 10 mice treated with 200 mg/kg experienced a complete regression of their tumors; only 3 mice in 75 mg/kg group and 1 mouse in the 200 mg/kg group experienced a minor regrowth of their tumors at the completion of observation period. Treatment with 50 mg/kg SGI-1776 on a daily schedule or 100 mg/kg on a biweekly schedule resulted in some antitumor effect; no regressions were observed on day 18 but a significant 13% T/C after 50 mg/kg and 11% after 100 mg/kg was observed on day 22. Of note was the observation that potent efficacy was achieved with an intermittent treatment schedule (2 oral doses/wk) at 100 or 200 mg/kg. Reference: Blood. 2011 Jul 21; 118(3): 693–702. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3142906/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 103.0 | 254.06 | |
| Ethanol | 81.0 | 199.79 |
The following data is based on the product molecular weight 405.42 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. Wen QL, Yi HQ, Yang K, Yin CT, Yin WJ, Xiang FY, Bao M, Shuai J, Song YW, Ge MH, Zhu X. Role of oncogene PIM-1 in the development and progression of papillary thyroid carcinoma: Involvement of oxidative stress. Mol Cell Endocrinol. 2021 Mar 1;523:111144. doi: 10.1016/j.mce.2020.111144. Epub 2020 Dec 28. PMID: 33383107. 2. Hou X, Yu Y, Feng J, Wang J, Zheng C, Ling Z, Ge M, Zhu X. Biochemical changes of salivary gland adenoid cystic carcinoma cells induced by SGI-1776. Exp Cell Res. 2017 Mar 15;352(2):403-411. doi: 10.1016/j.yexcr.2017.02.029. Epub 2017 Feb 20. PMID: 28228352. 3. Chen LS, Redkar S, Taverna P, Cortes JE, Gandhi V. Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia. Blood. 2011 Jul 21;118(3):693-702. doi: 10.1182/blood-2010-12-323022. Epub 2011 May 31. PMID: 21628411; PMCID: PMC3142906. |
| In vitro protocol: | 1. Wen QL, Yi HQ, Yang K, Yin CT, Yin WJ, Xiang FY, Bao M, Shuai J, Song YW, Ge MH, Zhu X. Role of oncogene PIM-1 in the development and progression of papillary thyroid carcinoma: Involvement of oxidative stress. Mol Cell Endocrinol. 2021 Mar 1;523:111144. doi: 10.1016/j.mce.2020.111144. Epub 2020 Dec 28. PMID: 33383107. 2. Hou X, Yu Y, Feng J, Wang J, Zheng C, Ling Z, Ge M, Zhu X. Biochemical changes of salivary gland adenoid cystic carcinoma cells induced by SGI-1776. Exp Cell Res. 2017 Mar 15;352(2):403-411. doi: 10.1016/j.yexcr.2017.02.029. Epub 2017 Feb 20. PMID: 28228352. |
| In vivo protocol: | 1. Chen LS, Redkar S, Taverna P, Cortes JE, Gandhi V. Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia. Blood. 2011 Jul 21;118(3):693-702. doi: 10.1182/blood-2010-12-323022. Epub 2011 May 31. PMID: 21628411; PMCID: PMC3142906. |
1: Siu A, Virtanen C, Jongstra J. PIM kinase isoform specific regulation of MIG6 expression and EGFR signaling in prostate cancer cells. Oncotarget. 2011 Dec 22. [Epub ahead of print] PubMed PMID: 22193779.
2: Batra V, Maris JM, Kang MH, Reynolds CP, Houghton PJ, Alexander D, Kolb EA, Gorlick R, Keir ST, Carol H, Lock R, Billups CA, Smith MA. Initial testing (stage 1) of SGI-1776, a PIM1 kinase inhibitor, by the pediatric preclinical testing program. Pediatr Blood Cancer. 2011 Nov 2. doi: 10.1002/pbc.23364. [Epub ahead of print] PubMed PMID: 22052829.
3: Mahalingam D, Espitia CM, Medina EC, Esquivel JA 2nd, Kelly KR, Bearss D, Choy G, Taverna P, Carew JS, Giles FJ, Nawrocki ST. Targeting PIM kinase enhances the activity of sunitinib in renal cell carcinoma. Br J Cancer. 2011 Nov 8;105(10):1563-73. doi: 10.1038/bjc.2011.426. Epub 2011 Oct 20. PubMed PMID: 22015557; PubMed Central PMCID: PMC3242528.
4: Chen LS, Redkar S, Taverna P, Cortes JE, Gandhi V. Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia. Blood. 2011 Jul 21;118(3):693-702. Epub 2011 May 31. PubMed PMID: 21628411; PubMed Central PMCID: PMC3142906.
5: Chang M, Kanwar N, Feng E, Siu A, Liu X, Ma D, Jongstra J. PIM kinase inhibitors downregulate STAT3(Tyr705) phosphorylation. Mol Cancer Ther. 2010 Sep;9(9):2478-87. Epub 2010 Jul 28. PubMed PMID: 20667852.
6: Mumenthaler SM, Ng PY, Hodge A, Bearss D, Berk G, Kanekal S, Redkar S, Taverna P, Agus DB, Jain A. Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes. Mol Cancer Ther. 2009 Oct;8(10):2882-93. PubMed PMID: 19825806; PubMed Central PMCID: PMC2808126.
7: Chen LS, Redkar S, Bearss D, Wierda WG, Gandhi V. Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood. 2009 Nov 5;114(19):4150-7. Epub 2009 Sep 4. PubMed PMID: 19734450; PubMed Central PMCID: PMC2774551.
SGI-1776: results from the pediatric preclinical testing program. Researchers from Children's Hospital of Philadelphia recently reported that SGI-1776 exhibited cytotoxic activity in vitro with a median relative IC(50) of 3.1 µM. SGI-1776 induced significant differences in EFS distribution in vivo in 9 of 31 solid tumor xenografts and in 1 of 8 of the evaluable ALL xenografts. SGI-1776 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 1 of 39 evaluable models. In contrast, SGI-1776 induced complete responses of subcutaneous MV4;11 (B myeloid leukemia). (source: Pediatr Blood Cancer. 2011 Nov 2. doi: 10.1002/pbc.23364. [Epub ahead of print] )
Mechanisms of cytotoxicity: SGI-1776 in acute myeloid leukemia. Chen et al recently report that treatment of AML cells with SGI-1776 resulted in a concentration-dependent induction of apoptosis and we investigated its effect on Pim kinase functions. Phosphorylation of traditional Pim kinase targets, c-Myc(Ser62) and 4E-BP1 (Thr36/Thr47), were both decreased in actively cycling AML cell lines MV-4-11, MOLM-13 and OCI-AML-3. Levels of antiapoptotic proteins Bcl-2, Bcl-x(L), XIAP, and proapoptotic Bak and Bax were unchanged; however, a significant reduction in Mcl-1 was observed. This was correlated with inhibition of global RNA and protein synthesis and MCL-1 transcript decline after SGI-1776 treatment. These data suggest that SGI-1776 mechanism in AML involves Mcl-1 protein reduction. Consistent with cell line data, xenograft model studies with mice bearing MV-4-11 tumors showed efficacy with SGI-1776 . Importantly, SGI-1776 was also cytotoxic in AML primary cells, irrespective of FLT3 mutation status and resulted in Mcl-1 protein decline. (source: Blood. 2011 Jul 21;118(3):693-702. Epub 2011 May 31 .)
