BML-258 HCl
BML-258, also known as SK1-I, is a potent, water-soluble, isoenzyme-specific inhibitor of SphK1. In contrast to pan-SphK inhibitors, SK1-I did not inhibit SphK2, PKC, or numerous other protein kinases. SK1-I decreased growth and survival of human leukemia U937 and Jurkat cells, and enhanced apoptosis and cleavage of Bcl-2. Notably, SK1-I potently induced apoptosis in leukemic blasts isolated from patients with acute myelogenous leukemia but was relatively sparing of normal peripheral blood mononuclear leukocytes. Moreover, SK1-I markedly reduced growth of AML xenograft tumors. Specific inhibitors of SphK1 warrant attention as potential additions to the therapeutic armamentarium in leukemia.
1: Price MM, Oskeritzian CA, Falanga YT, Harikumar KB, Allegood JC, Alvarez SE, Conrad D, Ryan JJ, Milstien S, Spiegel S. A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell-dependent murine model of allergic asthma. J Allergy Clin Immunol. 2013 Feb;131(2):501-11.e1. doi: 10.1016/j.jaci.2012.07.014. Epub 2012 Aug 30. PubMed PMID: 22939756; PubMed Central PMCID: PMC3563730.
2: Nagahashi M, Ramachandran S, Kim EY, Allegood JC, Rashid OM, Yamada A, Zhao R, Milstien S, Zhou H, Spiegel S, Takabe K. Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Res. 2012 Feb 1;72(3):726-35. doi: 10.1158/0008-5472.CAN-11-2167. PubMed PMID: 22298596; PubMed Central PMCID: PMC3289261.
3: Cakir Z, Saydam G, Sahin F, Baran Y. The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60: acute myeloid leukemia cells. J Cancer Res Clin Oncol. 2011 Feb;137(2):279-86. doi: 10.1007/s00432-010-0884-x. Epub 2010 Apr 18. PubMed PMID: 20401667.
4: Kapitonov D, Allegood JC, Mitchell C, Hait NC, Almenara JA, Adams JK, Zipkin RE, Dent P, Kordula T, Milstien S, Spiegel S. Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res. 2009 Sep 1;69(17):6915-23. doi: 10.1158/0008-5472.CAN-09-0664. PubMed PMID: 19723667; PubMed Central PMCID: PMC2752891.
5: Paugh SW, Paugh BS, Rahmani M, Kapitonov D, Almenara JA, Kordula T, Milstien S, Adams JK, Zipkin RE, Grant S, Spiegel S. A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood. 2008 Aug 15;112(4):1382-91. doi: 10.1182/blood-2008-02-138958. Epub 2008 May 29. PubMed PMID: 18511810; PubMed Central PMCID: PMC2515133.
2: Nagahashi M, Ramachandran S, Kim EY, Allegood JC, Rashid OM, Yamada A, Zhao R, Milstien S, Zhou H, Spiegel S, Takabe K. Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Res. 2012 Feb 1;72(3):726-35. doi: 10.1158/0008-5472.CAN-11-2167. PubMed PMID: 22298596; PubMed Central PMCID: PMC3289261.
3: Cakir Z, Saydam G, Sahin F, Baran Y. The roles of bioactive sphingolipids in resveratrol-induced apoptosis in HL60: acute myeloid leukemia cells. J Cancer Res Clin Oncol. 2011 Feb;137(2):279-86. doi: 10.1007/s00432-010-0884-x. Epub 2010 Apr 18. PubMed PMID: 20401667.
4: Kapitonov D, Allegood JC, Mitchell C, Hait NC, Almenara JA, Adams JK, Zipkin RE, Dent P, Kordula T, Milstien S, Spiegel S. Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res. 2009 Sep 1;69(17):6915-23. doi: 10.1158/0008-5472.CAN-09-0664. PubMed PMID: 19723667; PubMed Central PMCID: PMC2752891.
5: Paugh SW, Paugh BS, Rahmani M, Kapitonov D, Almenara JA, Kordula T, Milstien S, Adams JK, Zipkin RE, Grant S, Spiegel S. A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. Blood. 2008 Aug 15;112(4):1382-91. doi: 10.1182/blood-2008-02-138958. Epub 2008 May 29. PubMed PMID: 18511810; PubMed Central PMCID: PMC2515133.
| Chemical | |
|---|---|
| CAS Num | 1072443-89-0 |
| Chemical Formula | C17H28ClNO2 |
| Molecular Weight | 313.86272 |
| IUPAC Chemical Name | (2R,3S,E)-2-(methylamino)-5-(4-pentylphenyl)pent-4-ene-1,3-diol hydrochloride |
| Elemental Analysis | C, 65.05; H, 8.99; Cl, 11.30; N, 4.46; O, 10.20 |
| Synonym | BML258; BML 258; BML-258; SK1I. |
| Solubility | Soluble in DMSO, not in water |
| SMILES Code | OC[C@@H](NC)[C@@H](O)/C=C/C1=CC=C(CCCCC)C=C1.[H]Cl |
| Biological | |
| Targets and Effects | N/A |
| Pathways | Apoptosis |
| Physical | |
| 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). |
| Shelf Life | >2 years if stored properly |
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