Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY Targeting MYC promoter G-quadruplex for MYC inhibition by Indenoisoquinolines G-quadruplex (G4) DNA is a globular DNA secondary structure and considered as a new class of molecular targets for anticancer drugs. MYC, one of the most commonly deregulated genes in human cancers, has a DNA G4 motif in its promoter that functions as a transcriptional silencer. Compounds that bind to and stabilize the G-quadruplex formed in the MYC promoter have been shown to significantly lower MYC levels in cancer cells. Thus, the MYC promoter G-quadruplex (MycG4) represents a novel target for MYC inhibition by small molecules. However, little is known about how MycG4 is regulated by proteins and development of MycG4- targeting drugs has been focused solely on G4 DNA. Whereas drug-DNA interactions may be insufficient for MYC inhibition, the effective mechanism of drug action could involve protein-DNA interactions, which is analogous to topoisomerase inhibitors. Very recently, we have discovered that indenoisoquinolines, a clinically tested scaffold with excellent drug-like properties, are strong MycG4 binders and potent MYC inhibitors. We have also discovered that the DDX5 helicase actively unfolds MycG4 and is critically involved in MYC gene transcriptional activation. These results provide new and critical insights to effectively downregulate MYC transcription by targeting MycG4 and its interactions with DDX5. Our central hypothesis is that indenoisoquinolines effectively suppress MYC transcription by binding to the MYC promoter G-quadruplex and disrupting DDX5-MycG4 interactions. The overall objective is to determine the molecular mechanism of effective MYC inhibition by indenoisoquinolines, establish the structure–activity relationships (SAR), and discover lead indenoisoquinolines for preclinical testing. The long-term research goal is to develop potent indenoisoquinoline MYC inhibitors as new anticancer drugs. The specific aims are: 1) Structural characterization of the MycG4-indenoisoquinoline complexes. 2) Establishing a compound library to determine indenoisoquinolines that bind MycG4 and inhibit MYC. 3) Determining the effect of MycG4-interactive indenoisoquinolines on DDX5 unfolding of the MYC promoter G4 and how this correlates with MYC suppression. 4) Designing and synthesizing optimized indenoisoquinolines for MYC suppression using structure-based rational approach; establishing SAR for MycG4-binding and inhibition of DDX5 unfolding. The expected outcome of this work is a determination of the SAR of indenoisoquinolines for MycG4-targeting, demonstration of the effective MYC suppression by inhibiting DDX5-MycG4 interaction, and discovery of lead compounds for future preclinical testing. The results will have an important positive impact because they lay the groundwork to develop new indenoisoquinoline anticancer drugs with MYC-targeted activity.
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