VER-155008

VER-155008 is an adenosine-derived inhibitor of heat shock protein 70 (Hsp70; IC₅₀ = 0.5 µM) that is selective over Hsp90.¹ It targets the nucleotide-binding domain (NBD) of Hsp70 and similarly binds the NBDs of Hsp70 cognates Hsc70 (K_i = 10 µM) and glucose-regulated protein 78 (Grp78; K_D = 80 nM).^2,3 VER-155008 inhibits the proliferation of human breast and colon cancer cell lines, inducing apoptosis or caspase-independent cell death.⁴ It induces the proteasome-dependent degradation of Hsp90 client proteins and potentiates the apoptotic activity of Hsp90 inhibitors.^1,4 VER-15508 also triggers paraptosis in anaplastic thyroid carcinoma cells.⁵

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1. Williamson, D.S., Borgognoni, J., Clay, A., et al. Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. J. Med. Chem. 52(6), 1510-1513 (2009).

2. Schlecht, R., Scholz, S.R., Dahmen, H., et al. Functional analysis of Hsp70 inhibitors. PLoS One 8(11), (2013).

3. Macias, A.T., Williamson, D.S., Allen, N., et al. Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity. J. Med. Chem. 54(12), 4034-4041 (2011).

4. Massey, A.J., Williamson, D.S., Browne, H., et al. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother. Pharmacol. 66(3), 535-545 (2015).

5. Kim, S.H., Kang, J.G., Kim, C.S., et al. The hsp70 inhibitor VER155008 induces paraptosis requiring de novo protein synthesis in anaplastic thyroid carcinoma cells. Biochim. Biophys. Acta 454(1), 36-41 (2014).