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Description: XMD8-92 (XMD-8-92) is a novel, potent and highly selective dual inhibitor of BMK1/ERK5 (big mitogen activated protein kinase 1 / extracellular-signal-regulated kinase) with potential antineoplastic activity. It inhibits BMK1/ERK5 with a Kd of 80 nM, and shows less potency against DCAMKL2, TNK1, and Plk4 (Kds of 190, 890, and 600 nM, respectively). It shows potent anti-proliferative activity in vitro and high in vivo antitumor efficacy in a pancreatic tumor xenograft model via a DCLK1-dependent mechanism. ERK5 pathway regulates transcription factors important for monocytic differentiation of human myeloid leukemia cells. The big mitogen activated protein kinase 1 (BMK1) pathway is the most recently discovered and least-studied mammalian mitogen-activated protein (MAP) kinase cascade, ubiquitously expressed in all types of cancer cells tested so far. Mitogens and oncogenic signals strongly activate this cellular MAP kinase pathway, thereby passing down proliferative, survival, chemoresistance, invasive, and angiogenic signals in tumor cells.
References: Cancer Cell. 2010 Sep 14;18(3):258-67; Cancer Lett. 2014 Aug 28;351(1):151-61.
Mass (g) = Concentration (mol/L) × Volume (L) × Molecular Weight (g/mol)
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
This equation is commonly abbreviated as: C1V1 = C2V2
In vitro activity: XMD8-92, via inhibition of BMK1 activation, significantly induces p21 expression in cells, and mediates suppression of cancer cell proliferation. XMD8-92 markedly abrogates the inhibitive effects of hydroxysafflor yellow A (HSYA) on hepatic stellate cell (HSC) activation, and blockes the HSYA-mediated MEF2C down-regulation.
Kinase Assay: KiNativ profiling of XMD8-92 is carried out with both an ATP and ADP acylphosphate-desthiobiotin with the following modifications. HeLa cell lysates (5 mg/mL total protein) are incubated in the presence of XMD8-92 at 50 μM, 10 μM, 2 μM, 0.8 μM, and 0 μM for 15 minutes prior to addition of the ATP or ADP acylphosphate probe (5 μM final probe concentration). All reactions are performed in duplicate. Probe reactions proceeded for 10 minutes and the reaction stopped by the addition of urea and processed for MS analysis. Samples are analyzed by LC-MS/MS on a linear ion trap mass spectrometer using a time segmented “target list” designed to collect MS/MS spectra from all kinase peptide-probe conjugates that can be detected in HeLa cell lysates. This target list is generated and validated by prior exhaustive analysis of HeLa lysates. Up to four characteristic fragment ions for each kinase peptide-probe conjugate are used to extract signals for each kinase, and a comparison of inhibitor treated to control (untreated) lysates allow for precise determination of % inhibition at each point. A manuscript describing the details of this targeted mass spectrometry approach is in preparation.
Purity ≥98%
COA
MSDS
NMR
Antitumor efficacy of XMD8-92. (A) A549 cells were injected subcutaneously into the flanks of Nod/Scid mice. (B) Mouse xenograft models were established as described in Experimental Procedures. (C) Fluorescence microscopy images of HeLa or LL/2 tumor sections from XMD8-92 treated or control mice as indicated. Cancer Cell. 2010 Sep 14;18(3):258-67.
Development of a Pharmacological Inhibitor of BMK1. (A) Chemical structure of XMD8-92.(B) HeLa cells were serum starved overnight followed by treatment with 1 or 5 μM XMD8-92 or 1 μM PD184352 as indicated for one hour. (C) HEK293 cells were co-transfected with expression plasmids of MEK5D and BMK1. Cancer Cell. 2010 Sep 14;18(3):258-67.
Activated BMK1 Translocates from the Cytosol to Colocalize with PML in the Nucleus.
BMK1 is in Complex with PML and Suppresses the Anti-Cancer Function of PML in Tumor Cells. Cancer Cell. 2010 Sep 14;18(3):258-67.
BMK1 Regulates PML Function through Phosphorylation. Cancer Cell. 2010 Sep 14;18(3):258-67.
Pharmacological inhibition of BMK1 suppresses tumor growth through PML. Cancer Cell. 2010 Sep 14;18(3):258-67.