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  SGI-1776

Description of SGI-1776: 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. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    SuperGen, Inc.

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.)

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.