AZD-1208
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.
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.
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.
| Chemical | |
|---|---|
| CAS Num | 1204144-28-4 |
| Chemical Formula | C21H21N3O2S |
| Molecular Weight | 379.48 |
| IUPAC Chemical Name | 5-[[2-[(3R)-3-Aminopiperidin-1-yl]biphenyl-3-yl]methylidene]-1,3-thiazolidine-2,4-dione |
| Exact Mass | 379.13545 |
| Elemental Analysis | C, 66.47; H, 5.58; N, 11.07; O, 8.43; S, 8.45 |
| Synonym | AZD1208 ; AZD-1208; AZD 1208. |
| Solubility | Soluble in DMSO, not in water |
| SMILES Code | O=C(NC/1=O)SC1=C/C2=C(N3C[C@H](N)CCC3)C(C4=CC=CC=C4)=CC=C2 |
| Biological | |
| Targets and Effects | N/A |
| Pathways | Apoptosis |
| Physical | |
| 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). |
| Shelf Life | >2 years if stored properly |
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