Development of DBHS-binding peptidomimetics for targeting telomerase-active cancers

Abstract

Telomeres are repetitive nucleoprotein structures that cap the ends of chromosomes and enable their replication without loss of genetic information. However, loss of telomeric repeats occurs with each replication of the chromosome, eventually resulting in replicative senescence or programmed cell death in some instances. Cancer cells harness non-conventional mechanisms to extend the length of their telomeres, thus circumventing and achieving unlimited replicative potential. Many human cancers, such as lung cancers and glioblastoma, utilise the telomerase holoenzyme to repair degraded telomeres, subsequently bypassing replicative limitations and allowing for indefinite proliferation. Proteins that are involved in the regulation of telomerase are thus potential drug targets for cancer therapy.

Recently, the protein NONO has been identified as a key facilitator in the assembly of the active telomerase core complex in cancer cells. Inhibition of NONO for cancer biology studies and eventually as a form of treatment for telomerase-active cancers is therefore attractive due to its intimate involvement in telomere control. This thesis describes efforts to discover the first molecular inhibitors of NONO by employing a range of drug discovery techniques including structure-based rational design, fragment-based drug discovery (FBDD), and cyclic peptide phage display.

The peptidomimetic compounds identified through these drug discovery techniques serve as the first known peptide-based binders of NONO to date. These results present the possibility of developing selective and potent inhibitors for NONO, providing a potential alternate route of therapy to treat telomerase-active cancers.