The <i>c-myc</i> oncogene is considered to be a master regulator of gene expression, and as such its overexpression is associated with the dysfunctional cell growth in cancer. The c-myc oncogene also adopts a unique conformation, a G-quadruplex DNA, which was thought to hold promise for the development of selective inhibitors. However, putative G4 forming sequences have been now established to be widely distributed in the genome, and since all G4 motifs contain a common feature, the G-tetrad, selectivity comes down to a difficult problem of recognizing the subtle differences in the connecting loops.<br/>We have previously reported on the synthesis and SAR of Aryl-Isoxazolyl Amides (AIMs), and have evidenced their interaction with G4-DNA by several methods. Substitution at the C-10 position of the AIM produced analogs with robust activity against tumor cell lines in the NCI60. While docking studies indicated reasonable agreement with the actual pharmacology observed, the G4 is thought to act as an off switch for gene expression in a conformationally dynamic process, which requires unfolding to initiate sequence reading. To address these conformational dynamics, we have undertaken a molecular dynamics study using the crystallographic coordinates recently reported by Stump, et al, (pdb accession 6AU4), using the YASARA platform, which is based on an AMBER forcefield. Over the course of 20 ns, the G4 was observed to partially unfold, and then re-fold, which opens up space for the N-Het-AIM to conformationally accommodate the G4 in an induced fit manner. The study indicates several features which are predicable or even expected from what is already known from the small molecule binding DNA precedent. However, the dynamics also suggest some unique features which the N-Het-AIMs possess which could plausibly contribute to their utility. The use of the model to explain known previous observations and predict new directions will be discussed.

Molecular dynamics study of N-Heterocyclic Aryl Isoxazole Amides (AIMs) at the c-myc oncogene

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.