Discovery of highly selective inhibitors of calmodulin-dependent kinases that restore insulin sensitivity in the diet-induced obese in vivo mouse model

Research output: Contribution to journalArticlepeer-review

Authors

  • Christophe Fromont
  • Alessio Atzori
  • Divneet Kaur
  • Lubna Hashmi
  • Alejandro Cabanillas
  • Huy Van Nguyen
  • D Heulyn Jones
  • Miguel Garzón
  • Ana Varela
  • Brett Stevenson
  • Greg Iacobini
  • Sundaresan Rajesh
  • Jitendra Kumar
  • Paige Grant
  • Juliet Morgan
  • Fiona Sorrell
  • Clara Redondo
  • Andreas Kramer
  • C John Harris
  • Brendan Leighton
  • Sharon Cheetham
  • Colin Kenyon
  • Anna M Grabowska
  • Michael Overduin
  • Fedor Berditchevski
  • Christopher Weston
  • Stefan Knapp
  • Peter M Fischer
  • Sam Butterworth

Abstract

Polymorphisms in the region of the calmodulin-dependent kinase isoform D (CaMK1D) gene are associated with increased incidence of diabetes, with the most common polymorphism resulting in increased recognition by transcription factors and increased protein expression. While reducing CaMK1D expression has a potentially beneficial effect on glucose processing in human hepatocytes, there are no known selective inhibitors of CaMK1 kinases that can be used to validate or translate these findings. Here we describe the development of a series of potent, selective and drug-like CaMK1 inhibitors that are able to provide significant free target cover in mouse models and are therefore useful as in vivo tool compounds. Our results show that a lead compound from this series improves insulin sensitivity and glucose control in the diet-induced obesity mouse model after both acute and chronic administration, providing the first in vivo validation of CaMK1D as a target for diabetes therapeutics.

Details

Original languageEnglish
JournalJournal of Medicinal Chemistry
Publication statusE-pub ahead of print - 20 May 2020