1. Academic Validation
  2. BET bromodomain inhibitors regulate keratinocyte plasticity

BET bromodomain inhibitors regulate keratinocyte plasticity

  • Nat Chem Biol. 2021 Mar;17(3):280-290. doi: 10.1038/s41589-020-00716-z.
Gabi Schutzius 1 Christian Kolter 1 Sebastian Bergling 1 Federico Tortelli 1 Florian Fuchs 1 Steffen Renner 1 Vito Guagnano 1 Simona Cotesta 1 Heinrich Rueeger 1 Michael Faller 1 Laure Bouchez 1 Adrian Salathe 1 Florian Nigsch 1 Shola M Richards 1 Malvina Louis 1 Viktoria Gruber 1 Alexandra Aebi 1 Jonathan Turner 1 Frederic Grandjean 1 Jun Li 2 Chris Dimitri 2 3 Jason R Thomas 2 Markus Schirle 2 Jutta Blank 1 Peter Drueckes 1 Andrea Vaupel 1 Ralph Tiedt 1 Paul W Manley 1 Julia Klopp 1 Rene Hemmig 1 Florence Zink 1 Nelly Leroy 1 Walter Carbone 1 Guglielmo Roma 1 Caroline Gubser Keller 1 Natalie Dales 2 Armin Beyerbach 1 Alfred Zimmerlin 1 Debora Bonenfant 1 Remi Terranova 1 Amy Berwick 2 Sukhdeep Sahambi 2 Aimee Reynolds 2 Lori L Jennings 2 Heinz Ruffner 1 Peter Tarsa 2 Tewis Bouwmeester 1 Vickie Driver 2 Mathias Frederiksen 1 Felix Lohmann 4 Susan Kirkland 5 6
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 2 Novartis Institutes for BioMedical Research, Cambridge, Cambridge, MA, USA.
  • 3 GlaxoSmithKline, Cambridge, MA, USA.
  • 4 Novartis Institutes for BioMedical Research, Basel, Switzerland. Felix.Lohmann@novartis.com.
  • 5 Novartis Institutes for BioMedical Research, Basel, Switzerland. Susan.Kirkland@harvantispharma.co.uk.
  • 6 Harvantis Pharma Consulting Ltd, London, UK. Susan.Kirkland@harvantispharma.co.uk.
Abstract

Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class.

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