Evaluation of WO2014207069 A1: Multitarget Hedgehog pathway inhibitors and uses thereof

Expert Opin Ther Pat. 2016;26(4):529-35. doi: 10.1517/13543776.2016.1132309. Epub 2016 Feb 16.

Abstract

In recent years, the involvement of the Hedgehog (Hh) signaling pathway in various human diseases and dysfunctions has been clearly demonstrated. Smoothened (Smo), one of the upstream signal transducers, has been the most druggable target of the Hh pathway. However, the emergence of resistance to Smo inhibitors and the identification of Smo-independent activation of the Hh pathway led to the need to find new chemical entities able to interfere with downstream components, such as Gli. For this purpose, two different computational approaches have been applied to a small-sized library of natural compounds. As a result, an isoflavone derivative that showed ability to inhibit both Smo and Gli1 has been identified; namely, Glabrescione B. A new synthetic approach has been planned for this compound and its derivatives. Biological evaluation demonstrated the mechanism of action and showed a promising preclinical profile.

Keywords: Gli1 inhibitors; Hedgehog signaling pathway; Hedgehog-dependent cancers; isoflavone; naturally occurring molecules.

MeSH terms

  • Animals
  • Chromones / chemical synthesis
  • Chromones / pharmacology
  • Drug Design*
  • Hedgehog Proteins / antagonists & inhibitors*
  • Hedgehog Proteins / metabolism
  • Humans
  • Isoflavones / chemical synthesis
  • Isoflavones / pharmacology
  • Patents as Topic
  • Signal Transduction / drug effects
  • Small Molecule Libraries
  • Smoothened Receptor / antagonists & inhibitors*
  • Zinc Finger Protein GLI1 / antagonists & inhibitors

Substances

  • Chromones
  • Hedgehog Proteins
  • Isoflavones
  • SMO protein, human
  • Small Molecule Libraries
  • Smoothened Receptor
  • Zinc Finger Protein GLI1
  • glabrescione B