10074-G5

10074-G5 is a c-Myc inhibitor that binds to and distorts the bHLH-ZIP domain of c-Myc (K_d = 2.8 µM), thereby inhibiting c-Myc/Max heterodimer formation and inhibiting its transcriptional activity (IC₅₀ = 146 µM).^1,2,3 10074-G5 is cytotoxic to c-Myc-overexpressing cells lines with IC₅₀ values of 15.6 and 13.5 µM for Daudi Burkitt lymphoma cells and HL60 promyelocytic leukemia cells, respectively.⁴ 10074-G5 can also interfere with N-Myc/Max interactions (K_d = 19.2 µM for binding the bHLH-Zip of N-Myc), inducing apoptosis in N-Myc amplified neuroblastoma Kelly cells (IC₅₀ = 22.5 µM).⁵

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1. Follis, A.V., Hammoudeh, D.I., Wang, J., et al. Structural rationale for the coupled binding and unfolding of the c-Myc oncoprotein by small molecules. Chem. Biol. 15(11), 1149-1155 (2008).

2. Hammoudeh, D.I., Follis, A.V., Prochownik, E.V., et al. Multiple independent binding sites for small-molecule inhibitors on the oncoprotein c-Myc. J. Am. Chem. Soc. 131(21), 7391-7401 (2009).

3. Yap, J.L., Wang, H., Hu, A., et al. Pharmacophore identification of c-Myc inhibitor 10074-G₅. Bioorg. Med. Chem. Lett. 23(1), 370-374 (2013).

4. Clausen, D.M., Guo, J., Parise, R.A., et al. In vitro cytotoxicity and in vivo efficacy, pharmacokinetics, and metabolism of 10074-G₅, a novel small-molecule inhibitor of c-Myc/Max dimerization. J. Pharmacol. Exp. Ther. 335(3), 715-727 (2010).

5. Müller, I., Larsson, K., Frenzel, A., et al. Targeting of the MYCN protein with small molecule c-MYC inhibitors. PLoS One 9(5), (2014).