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Application of computer-aided drug discovery methods for targeting the oncogenic activity of Myc in prostate cancer

University of British Columbia

To date, castration-resistant prostate cancer (CRPC) remains an incurable disease, as conventional therapeutic inhibition of androgen receptor (AR) signaling with anti-androgens inevitably leads to treatment-resistance, further progression to final stage neuroendocrine prostate cancer (NEPC), and rapid demise. Therefore, development of novel targeted therapies for CRPC and NEPC is of paramount importance. Targeting the oncogenic activity of Myc family of transcription factors has long been and currently is a major topic of cancer research. While Myc is an essential regulator of normal growth, its exacerbated expression is a hallmark of human cancer. Amplifications of Myc family members play critical roles in prostate cancer progression and therapy-resistance. c-Myc is amplified across its full-spectrum and has special relevance in CRPC as it positively regulates the expression and activity of AR itself as well as of ligand-independent AR-V truncated variants, such as AR-V7 that confers resistance to anti-androgens. Moreover, N-Myc amplifications induce NEPC phenotype. Although Myc proteins are high-value targets for therapeutic intervention, clinically viable Myc-directed inhibitors await discovery. Intrinsically disordered, Myc lacks effective binding pockets. Therefore, the use of conventional methods of structure-based drug discovery is an inherent challenge. Moreover, the oncogenic function of Myc is dependent on its dimerization with the obligate partner Max, which together form a functional transcriptional complex capable of activating critical genomic targets and eliciting oncogenic effects. This dissertation describes the discovery and development of novel small-molecule inhibitors targeting the oncogenic activity of Myc-Max complexes. Specifically, we utilized methods of computer-aided drug discovery (CADD) to target directly complexes of c-Myc and N-Myc with Max, as well as Myc-upregulated hnRNP A1 splicing factor. The use of CADD enabled us to identify small-molecule drug candidates, which selectively disrupt critical protein-nucleic acid interactions – a therapeutic approach that has not been previously exercised for these targets. The CADD techniques encompassed large-scale structure-based docking and molecular dynamics simulations along with ligand-based approaches including pharmacophore modeling, chemical similarity searches and ADMET profiling, complemented by experimental validation. On the outlook, the identified lead inhibitors lay the foundation for development of safe and effective clinical candidates that may serve as prospective therapeutics for CRPC and NEPC.

Text

2021-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71357

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/