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Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors.

ABSTRACT: Reversible glycosylation of nuclear and cytoplasmic proteins is an important regulatory mechanism across metazoans. One enzyme, O-linked N-acetylglucosamine transferase (OGT), is responsible for all nucleocytoplasmic glycosylation and there is a well-known need for potent, cell-permeable inhibitors to interrogate OGT function. Here we report the structure-based evolution of OGT inhibitors culminating in compounds with low nanomolar inhibitory potency and on-target cellular activity. In addition to disclosing useful OGT inhibitors, the structures we report provide insight into how to inhibit glycosyltransferases, a family of enzymes that has been notoriously refractory to inhibitor development.

SUBMITTER: Martin SES

PROVIDER: S-EPMC6261342 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Structure-Based Evolution of Low Nanomolar O-GlcNAc Transferase Inhibitors.

Martin Sara E S SES Tan Zhi-Wei ZW Itkonen Harri M HM Duveau Damien Y DY Paulo Joao A JA Janetzko John J Boutz Paul L PL Törk Lisa L Moss Frederick A FA Thomas Craig J CJ Gygi Steven P SP Lazarus Michael B MB Walker Suzanne S

Journal of the American Chemical Society 20181004 42

Reversible glycosylation of nuclear and cytoplasmic proteins is an important regulatory mechanism across metazoans. One enzyme, O-linked N-acetylglucosamine transferase (OGT), is responsible for all nucleocytoplasmic glycosylation and there is a well-known need for potent, cell-permeable inhibitors to interrogate OGT function. Here we report the structure-based evolution of OGT inhibitors culminating in compounds with low nanomolar inhibitory potency and on-target cellular activity. In addition ...[more]

PMID: 30285435

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