Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2.

Autor: Mares A; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Miah AH; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Smith IED; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Rackham M; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Thawani AR; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Cryan J; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Haile PA; Innate Immunity Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA., Votta BJ; Innate Immunity Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA., Beal AM; Innate Immunity Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA., Capriotti C; Innate Immunity Research Unit, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA., Reilly MA; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA., Fisher DT; Drug Design and Selection, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA, 19426, USA., Zinn N; Cellzome, a GSK company, Meyerhofstrasse 1, 69117, Heidelberg, Germany., Bantscheff M; Cellzome, a GSK company, Meyerhofstrasse 1, 69117, Heidelberg, Germany., MacDonald TT; Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, London, UK., Vossenkamper A; Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, London, UK., Dace P; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Churcher I; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Benowitz AB; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Watt G; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Denyer J; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Scott-Stevens P; Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK., Harling JD; Medicine Design, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK. john.d.harling@gsk.com.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2020 Mar 20; Vol. 3 (1), pp. 140. Date of Electronic Publication: 2020 Mar 20.
DOI: 10.1038/s42003-020-0868-6
Abstrakt: Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.
Databáze: MEDLINE
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