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Discovery of drugs that directly target the intrinsically disordered region of the androgen receptor.

ABSTRACT: Introduction: Intrinsically disordered proteins (IDPs) and regions (IDRs) lack stable three-dimensional structure making drug discovery challenging. A validated therapeutic target for diseases such as prostate cancer is the androgen receptor (AR) which has a disordered amino-terminal domain (NTD) that contains all of its transcriptional activity. Drug discovery against the AR-NTD is of intense interest as a potential treatment for disease such as advanced prostate cancer that is driven by truncated constitutively active splice variants of AR that lack the C-terminal ligand-binding domain (LBD).Areas covered: This article presents an overview of the relevance of AR and its intrinsically disordered NTD as a drug target. AR structure and approaches to blocking AR transcriptional activity are discussed. The discovery of small molecules, including the libraries used, proven binders to the AR-NTD, and site of interaction of these small molecules in the AR-NTD are presented along with discussion of the Phase I clinical trial.Expert opinion: The lack of drugs in the clinic that directly bind IDPs/IDRs reflects the difficulty of targeting these proteins and obtaining specificity. However, it may also point to an inappropriateness of too closely borrowing concepts and resources from drug discovery to folded proteins.

SUBMITTER: Sadar MD

PROVIDER: S-EPMC8693730 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Since the beginning of the COVID-19 pandemic caused by SARS-CoV-2, millions of patients have been diagnosed and many of them have died from the disease worldwide. The identification of novel therapeutic targets are of utmost significance for prevention and treatment of COVID-19. SARS-CoV-2 is a single-stranded RNA virus with a 30 kb genome packaged into a membrane-enveloped virion, transcribing several tens of proteins. The belief that the amino acid sequence of proteins determines their 3D structure which, in turn, determines their function has been a central principle of molecular biology for a long time. Recently, it has been increasingly realized, however, that there is a large group of proteins that lack a fixed or ordered 3D structure, yet they exhibit important biological activities─so-called intrinsically disordered proteins and protein regions (IDPs/IDRs). Disordered regions in viral proteins are generally associated with viral infectivity and pathogenicity because they endow the viral proteins the ability to easily and promiscuously bind to host proteins; therefore, the proteome of SARS-CoV-2 has been thoroughly examined for intrinsic disorder. It has been recognized that, in fact, the SARS-CoV-2 proteome exhibits significant levels of structural order, with only the nucleocapsid (N) structural protein and two of the nonstructural proteins being highly disordered. The spike (S) protein of SARS-CoV-2 exhibits significant levels of structural order, yet its predicted percentage of intrinsic disorder is still higher than that of the spike protein of SARS-CoV. Noteworthy, however, even though IDPs/IDRs are not common in the SARS-CoV-2 proteome, the existing ones play major roles in the functioning and virulence of the virus and are thus promising drug targets for rational antiviral drug design. Presented here is a COVID-19 perspective on the intrinsically disordered proteins, summarizing recent results on the SARS-CoV-2 proteome disorder features, their physiological and pathological relevance, and their prominence as prospective drug target sites.

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Discovery of drugs that directly target the intrinsically disordered region of the androgen receptor.

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