Myc is a transcription factor of the basic-helix-loop-helix-leucine zipper (b-HLH-LZ) protein family that has essential roles in cellular growth, proliferation, and apoptosis. In order to function, Myc must heterodimerize with Max, another b-HLH-LZ protein. Overexpression of Myc has been associated with the pathogenesis of a variety of human cancers. Therefore, Myc inhibition appears to be an attractive approach for novel cancer therapies [1]. One strategy in this regard is to target Myc-Max heterodimerization. Despite the difficulty of disrupting the large interaction interface of the heterodimer, there is proof-of-concept documenting that small molecule inhibitors can be effective in vitro. However, most of the existing Myc inhibitors exhibit limited effectiveness in vivo. Based on our previous successful treatment of mouse pancreatic cancer with a small molecule Myc inhibitor (Mycro3; [1]), we use computer-aided drug design in order to develop and optimize novel inhibitors of the Myc-Max heterodimerization that would be effective in tumor regression. For this purpose, we have developed a novel structure- and ligand-based drug design protocol. In the structure-based approach, we utilized the three distinct binding sites on the monomeric Myc bHLH-LZ domain reported in the literature, and a virtual screening campaign was launched on each monomeric peptide fragment. Subsequently, utilizing a ligand-based approach, we used Mycro3 as a query structure to conduct a 3D-pharmacophore similarity screening for the top-scored virtual screening results for Myc402-412, the site where most known Myc inhibitors bind. The compounds were post processed using the ChemBioServer platform and subjected to property filtering [2]. From the combined structure- and ligand- based screenings on Myc402-412, 11 potential inhibitors were identified and purchased for in vitro testing. Cell-based in vitro assays were performed with the TGR-1 (Myc+/+) and the HO15.19 (Myc-/-; control) cell lines. These assays identified a novel anti-Myc inhibitor with activity in the low micromolar range and a large “window” of specificity. References [1] D. Stellas et al., Therapeutic effects of an anti-myc drug on mouse pancreatic cancer., J. Natl. Cancer Inst. 2014, 106(12), pii: dju320. [2] E. Athanasiadis et al., ChemBioServer: a web-based pipeline for filtering, clustering and visualization of chemical compounds used in drug discovery. Bioinformatics, 2012, 28, (22), 3002-3003.

Discovery of novel Myc inhibitors using structure and ligand-based drug design

251st National Meeting (2016)

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