XMD8-92

XMD8-92 is an ERK5 inhibitor (K_d = 80 nM) that less potently inhibits DCAMKL2, TNK1, and Plk4 (K_ds = 190, 890, and 600 nM, respectively) in a panel of 402 kinases.¹ It blocks ERK5 autophosphorylation, ERK5-mediated phosphorylation of promyelocytic leukemia protein (PML), and PML-dependent activation of p21.¹ XMD8-92 inhibits AP-1 transcriptional activity induced by MEK5-activated ERK5 but not that induced by Cdc37.² It inhibits bFGF-induced angiogenesis in a Matrigel^™ plug assay in mice and reduces tumor growth in a HeLa mouse xenograft model when administered at a dose of 50 mg/kg twice per day.¹ XMD8-92 also binds bromodomain-containing protein 4 (BRD4; K_d = 170 nM for BRD4 bromodomain 1).³

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1. Yang, Q., Deng, X., Lu, B., et al. Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein. Cancer Cell 18(3), 258-267 (2010).

2. Erazo, T., Moreno, A., Ruiz-Babot, G., et al. Canonical and kinase activity-independent mechanisms for extracellular signal-regulated kinase 5 (ERK5) nuclear translocation require dissociation of Hsp90 from the ERK5-Cdc37 complex. Mol. Cell Biol. 33(8), 1671-1686 (2013).

3. Lin, E.C.K., Amantea, C.M., Nomanbhoy, T.K., et al. ERK5 kinase activity is dispensable for cellular immune response and proliferation. Proc. Natl. Acad. Sci. USA 113(42), 11865-11870 (2016).