BL-8040

• CAT Number: I004334
• CAS Number: 664334-36-5
• Molecular Formula: C97H144FN33O19S2
• Molecular Weight: 2159.52
• Purity: ≥95%
• Target: CXCR
• Solubility: Soluble in DMSO, not in water
• Storage: Store at -20°C
• InChI: InChI=1S/C97H144FN33O19S2/c98-60-33-31-58(32-34-60)78(135)119-65(19-8-42-113-93(104)105)79(136)121-68(21-10-44-115-95(108)109)83(140)126-73(51-56-25-30-57-14-1-2-15-59(57)48-56)87(144)130-75-53-152-151-52-74(88(145)118-63(77(101)134)18-7-41-112-92(102)103
• InChIKey: JJVZSYKFCOBILL-MKMRYRNGSA-N
• SMILES: NCCCC[C@@H]1NC(=O)[C@H](CCCNC(=O)N)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](CSSC[C@H](NC(=O)[C@H](CCCNC(=O)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc3ccc(O)cc3)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CCCCN)NC1=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N)NC(=O)[C@H](Cc5ccc6ccccc6c5)NC

BL-8040, also known as BKT140 and TF 14016, is an orally bioavailable inhibitor of CXC Chemokine Receptor 4 (CXCR4) with potential antineoplastic activity. CXCR4 antagonist BKT140 selectively binds to the chemokine receptor CXCR4, preventing the binding of stromal derived factor-1 (SDF-1 or CXCL12) to the CXCR4 receptor and subsequent receptor activation, which may result in decreased tumor cell proliferation and migration. In addition, inhibition of CXCR4 may induce mobilization of hematopoietic cells from the bone marrow into blood. The G protein-coupled receptor CXCR4 plays an important role in chemotaxis and angiogenesis and is upregulated in several tumor cell types; SDF-1/CXCR4 interaction induces retention of hematopoietic cells in the bone marrow.

Reference

1:Leukemia. 2017 Apr 7. doi: 10.1038/leu.2017.82. [Epub ahead of print] The CXCR4 inhibitor BL-8040 induces the apoptosis of AML blasts by downregulating ERK, BCL-2, MCL-1 and cyclin-D1 via altered miR-15a/16-1 expression.Abraham M,Klein S,Bulvik B,Wald H,Weiss ID,Olam D,Weiss L,Beider K,Eizenberg O,Wald O,Galun E,Avigdor A,Benjamini O,Nagler A,Pereg Y,Tavor S,Peled A, PMID: 28280274 DOI: 10.1038/leu.2017.82
Abstract: CXCR4 is a key player in the retention and survival of human acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment. We studied the effects of the CXCR4 antagonist BL-8040 on the survival of AML blasts, and investigated the molecular mechanisms by which CXCR4 signaling inhibition leads to leukemic cell death. Treatment with BL-8040 induced the robust mobilization of AML blasts from the BM. In addition, AML cells exposed to BL-8040 underwent differentiation. Furthermore, BL-8040 induced the apoptosis of AML cells in vitro and in vivo. This apoptosis was mediated by the upregulation of miR-15a/miR-16-1, resulting in downregulation of the target genes BCL-2, MCL-1 and cyclin-D1. Overexpression of miR-15a/miR-16-1 directly induced leukemic cell death. BL-8040-induced apoptosis was also mediated by the inhibition of survival signals via the AKT/ERK pathways. Importantly, treatment with a BCL-2 inhibitor induced apoptosis and act together with BL-8040 to enhance cell death. BL-8040 also synergized with FLT3 inhibitors to induce AML cell death. Importantly, this combined treatment prolonged the survival of tumor-bearing mice and reduced minimal residual disease in vivo. Our results provide a rationale to test combination therapies employing BL-8040 and BCL-2 or FLT3 inhibitors to achieve increased efficacy of these agents.Leukemia advance online publication, 7 April 2017; doi:10.1038/leu.2017.82.