WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205763
CAS#: 1204144-28-4
Description: AZD1208 is orally available, small molecule inhibitor of PIM kinases with potential antineoplastic activity. Pan-PIM kinase inhibitor AZD1208 inhibits the activities of PIM1, PIM2 and PIM3 serine/threonine kinases, which may result in the interruption of the G1/S phase cell cycle transition, thereby causing cell cycle arrest and inducing apoptosis in cells that overexpress PIMs. The growth inhibition of several leukemia cell lines by this agent is correlated with the expression levels of PIM1, which is the substrate of STAT transcription factors. PIM kinases are downstream effectors of many cytokine and growth factor signaling pathways and are upregulated in various malignancies.
MedKoo Cat#: 205763
Name: AZD-1208
CAS#: 1204144-28-4
Chemical Formula: C21H21N3O2S
Exact Mass: 379.13545
Molecular Weight: 379.48
Elemental Analysis: C, 66.47; H, 5.58; N, 11.07; O, 8.43; S, 8.45
Synonym: AZD1208 ; AZD-1208; AZD 1208.
IUPAC/Chemical Name: 5-[[2-[(3R)-3-Aminopiperidin-1-yl]biphenyl-3-yl]methylidene]-1,3-thiazolidine-2,4-dione
InChi Key: MCUJKPPARUPFJM-UWCCDQBKSA-N
InChi Code: InChI=1S/C21H21N3O2S/c22-16-9-5-11-24(13-16)19-15(12-18-20(25)23-21(26)27-18)8-4-10-17(19)14-6-2-1-3-7-14/h1-4,6-8,10,12,16H,5,9,11,13,22H2,(H,23,25,26)/b18-12-/t16-/m1/s1
SMILES Code: O=C(NC/1=O)SC1=C/C2=C(N3C[C@H](N)CCC3)C(C4=CC=CC=C4)=CC=C2
Appearance: Light yellow 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: | AZD1208 is a Pim kinase inhibitor with IC50s of 0.4 nM, 5 nM, and 1.9 nM for Pim1, Pim2, and Pim3 in cell-free assays, respectively. |
| In vitro activity: | To determine the cytotoxicity resulting from AZD1208 treatment, endogenous cell death was subtracted from the cytotoxicity of each CLL (chronic lymphocytic leukemia) sample. Cells from healthy donors treated with either 3-µM or 10-µM AZD1208 had an average 2% cell death rate, whereas CLL cells had a 6% cell death rate when treated with 3-µM AZD1208 and an 18% cell death rate when treated with 10-µM AZD1208. These data clearly suggest that AZD1208 causes negligible cytotoxicity in healthy peripheral blood lymphocytes and moderate cell death in malignant CLL lymphocytes. Reference: Oncotarget. 2019 Apr 19;10(29):2793-2809. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497463/ |
| In vivo activity: | The therapeutic effect of the Pim-1 inhibitor AZD1208 was assessed in a lupus-prone (NZB × NZW)F1 mouse model (n = 10 mice per group). AZD1208 reduced the severity of proteinuria, glomerulonephritis, renal immune complex deposits, and serum anti-dsDNA antibody levels, concomitant with the suppression of NFATc1 expression and NLRP3 inflammasome activation, in diseased (NZB × NZW)F1 mice (each P < 0.05 versus controls). Reference: Arthritis Rheumatol. 2019 Aug;71(8):1308-1318. https://onlinelibrary.wiley.com/doi/abs/10.1002/art.40863 |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 37.57 | 99.0 | |
| DMSO:PBS (pH 7.2) (1:4) | 0.2 | 0.53 | |
| DMF | 0.1 | 0.26 |
The following data is based on the product molecular weight 379.48 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. Cervantes-Gomez F, Stellrecht CM, Ayres ML, Keating MJ, Wierda WG, Gandhi V. PIM kinase inhibitor, AZD1208, inhibits protein translation and induces autophagy in primary chronic lymphocytic leukemia cells. Oncotarget. 2019 Apr 19;10(29):2793-2809. doi: 10.18632/oncotarget.26876. PMID: 31073371; PMCID: PMC6497463. 2. Yadav AK, Kumar V, Bailey DB, Jang BC. AZD1208, a Pan-Pim Kinase Inhibitor, Has Anti-Growth Effect on 93T449 Human Liposarcoma Cells via Control of the Expression and Phosphorylation of Pim-3, mTOR, 4EBP-1, S6, STAT-3 and AMPK. Int J Mol Sci. 2019 Jan 16;20(2):363. doi: 10.3390/ijms20020363. PMID: 30654529; PMCID: PMC6359068. 3. Fu R, Xia Y, Li M, Mao R, Guo C, Zhou M, Tan H, Liu M, Wang S, Yang N, Zhao J. Pim-1 as a Therapeutic Target in Lupus Nephritis. Arthritis Rheumatol. 2019 Aug;71(8):1308-1318. doi: 10.1002/art.40863. Epub 2019 Jul 2. PMID: 30791224. |
| In vitro protocol: | 1. Cervantes-Gomez F, Stellrecht CM, Ayres ML, Keating MJ, Wierda WG, Gandhi V. PIM kinase inhibitor, AZD1208, inhibits protein translation and induces autophagy in primary chronic lymphocytic leukemia cells. Oncotarget. 2019 Apr 19;10(29):2793-2809. doi: 10.18632/oncotarget.26876. PMID: 31073371; PMCID: PMC6497463. 2. Yadav AK, Kumar V, Bailey DB, Jang BC. AZD1208, a Pan-Pim Kinase Inhibitor, Has Anti-Growth Effect on 93T449 Human Liposarcoma Cells via Control of the Expression and Phosphorylation of Pim-3, mTOR, 4EBP-1, S6, STAT-3 and AMPK. Int J Mol Sci. 2019 Jan 16;20(2):363. doi: 10.3390/ijms20020363. PMID: 30654529; PMCID: PMC6359068. |
| In vivo protocol: | 1. Fu R, Xia Y, Li M, Mao R, Guo C, Zhou M, Tan H, Liu M, Wang S, Yang N, Zhao J. Pim-1 as a Therapeutic Target in Lupus Nephritis. Arthritis Rheumatol. 2019 Aug;71(8):1308-1318. doi: 10.1002/art.40863. Epub 2019 Jul 2. PMID: 30791224. |
1: Kirschner AN, Wang J, van der Meer R, Anderson PD, Franco-Coronel OE, Kushner MH, Everett JH, Hameed O, Keeton EK, Ahdesmaki M, Grosskurth SE, Huszar D, Abdulkadir SA. PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer. J Natl Cancer Inst. 2014 Dec 13;107(2). pii: dju407. doi: 10.1093/jnci/dju407. PubMed PMID: 25505253; PubMed Central PMCID: PMC4326311.
2: Chen LS, Yang JY, Liang H, Cortes JE, Gandhi V. Protein profiling identifies mTOR pathway modulation and cytostatic effects of Pim kinase inhibitor, AZD1208, in acute myeloid leukemia. Leuk Lymphoma. 2016 Dec;57(12):2863-2873. PubMed PMID: 27054578.
3: Keeton EK, McEachern K, Dillman KS, Palakurthi S, Cao Y, Grondine MR, Kaur S, Wang S, Chen Y, Wu A, Shen M, Gibbons FD, Lamb ML, Zheng X, Stone RM, Deangelo DJ, Platanias LC, Dakin LA, Chen H, Lyne PD, Huszar D. AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood. 2014 Feb 6;123(6):905-13. doi: 10.1182/blood-2013-04-495366. PubMed PMID: 24363397; PubMed Central PMCID: PMC3916880.
4: Mazzacurati L, Lambert QT, Pradhan A, Griner LN, Huszar D, Reuther GW. The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells. Oncotarget. 2015 Nov 24;6(37):40141-57. doi: 10.18632/oncotarget.5653. PubMed PMID: 26472029; PubMed Central PMCID: PMC4741885.
5: Kreuz S, Holmes KB, Tooze RM, Lefevre PF. Loss of PIM2 enhances the anti-proliferative effect of the pan-PIM kinase inhibitor AZD1208 in non-Hodgkin lymphomas. Mol Cancer. 2015 Dec 8;14:205. doi: 10.1186/s12943-015-0477-z. PubMed PMID: 26643319; PubMed Central PMCID: PMC4672512.
6: Harada M, Benito J, Yamamoto S, Kaur S, Arslan D, Ramirez S, Jacamo R, Platanias L, Matsushita H, Fujimura T, Kazuno S, Kojima K, Tabe Y, Konopleva M. The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression. Oncotarget. 2015 Nov 10;6(35):37930-47. doi: 10.18632/oncotarget.6122. PubMed PMID: 26473447; PubMed Central PMCID: PMC4741975.
7: Tron AE, Keeton EK, Ye M, Casas-Selves M, Chen H, Dillman KS, Gale RE, Stengel C, Zinda M, Linch DC, Lai Z, Khwaja A, Huszar D. Next-generation sequencing identifies a novel ELAVL1-TYK2 fusion gene in MOLM-16, an AML cell line highly sensitive to the PIM kinase inhibitor AZD1208. Leuk Lymphoma. 2016 Dec;57(12):2927-2929. PubMed PMID: 27189703.
8: Doshi KA, Trotta R, Natarajan K, Rassool FV, Tron AE, Huszar D, Perrotti D, Baer MR. Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress. Oncotarget. 2016 Jul 26;7(30):48280-48295. doi: 10.18632/oncotarget.10209. PubMed PMID: 27374090; PubMed Central PMCID: PMC5217017.
9: Iqbal A, Eckerdt F, Bell J, Nakano I, Giles FJ, Cheng SY, Lulla RR, Goldman S, Platanias LC. Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110α inhibition. Oncotarget. 2016 May 31;7(22):33192-201. doi: 10.18632/oncotarget.8899. PubMed PMID: 27120806; PubMed Central PMCID: PMC5078085.
10: Brunen D, García-Barchino MJ, Malani D, Jagalur Basheer N, Lieftink C, Beijersbergen RL, Murumägi A, Porkka K, Wolf M, Zwaan CM, Fornerod M, Kallioniemi O, Martínez-Climent JÁ, Bernards R. Intrinsic resistance to PIM kinase inhibition in AML through p38α-mediated feedback activation of mTOR signaling. Oncotarget. 2016 Jun 21;7(25):37407-37419. doi: 10.18632/oncotarget.9822. PubMed PMID: 27270648; PubMed Central PMCID: PMC5122321.
11: Bellon M, Lu L, Nicot C. Constitutive activation of Pim1 kinase is a therapeutic target for adult T-cell leukemia. Blood. 2016 May 19;127(20):2439-50. doi: 10.1182/blood-2015-11-685032. PubMed PMID: 26813676; PubMed Central PMCID: PMC4874225.
12: Cen B, Xiong Y, Song JH, Mahajan S, DuPont R, McEachern K, DeAngelo DJ, Cortes JE, Minden MD, Ebens A, Mims A, LaRue AC, Kraft AS. The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling. Mol Cell Biol. 2014 Jul;34(13):2517-32. doi: 10.1128/MCB.00147-14. PubMed PMID: 24777602; PubMed Central PMCID: PMC4054323.
13: Cervantes-Gomez F, Lavergne B, Keating MJ, Wierda WG, Gandhi V. Combination of Pim kinase inhibitors and Bcl-2 antagonists in chronic lymphocytic leukemia cells. Leuk Lymphoma. 2015 Sep 28:1-9. [Epub ahead of print] PubMed PMID: 26088877; PubMed Central PMCID: PMC4814351.
14: Brasó-Maristany F, Filosto S, Catchpole S, Marlow R, Quist J, Francesch-Domenech E, Plumb DA, Zakka L, Gazinska P, Liccardi G, Meier P, Gris-Oliver A, Cheang MC, Perdrix-Rosell A, Shafat M, Noël E, Patel N, McEachern K, Scaltriti M, Castel P, Noor F, Buus R, Mathew S, Watkins J, Serra V, Marra P, Grigoriadis A, Tutt AN. PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. Nat Med. 2016 Nov;22(11):1303-1313. doi: 10.1038/nm.4198. PubMed PMID: 27775704.
15: Mo G, Gibbons F, Schroeder P, Krzyzanski W. Lifespan based pharmacokinetic-pharmacodynamic model of tumor growth inhibition by anticancer therapeutics. PLoS One. 2014 Oct 21;9(10):e109747. doi: 10.1371/journal.pone.0109747. PubMed PMID: 25333487; PubMed Central PMCID: PMC4204849.
AZD1208 is a potent ATP-competitive inhibitor of all three Pim kinase isoforms. The inhibitory constant (Ki) values were determined to be 0.1 nM for Pim-1, 1.92 nM for Pim-2, and 0.4 nM for Pim-3. In enzymatic assays carried out at Km ATP concentrations, AZD1208 inhibited kinase activity with an IC50 of 0.4 nM for Pim-1, 5.0 nM for Pim-2 and 1.9 nM for Pim-3. In enzyme assays using 5 mM ATP, the high end of physiological ATP concentration in human cells, the IC50 values were 2.6 nM for Pim-1, 164 nM for Pim-2, and 17 nM for Pim-3. ( Blood. 2013 Dec 20. [Epub ahead of print])
