PUBLICATION

Hedgehog antagonist pyrimidine-indole hybrid molecule inhibits ciliogenesis through microtubule destabilization

Authors
Sinha, S., Khatra, H., Khan, P.P., Pattanayak, S., Bhadra, J., Rather, B., Chakrabarti, S., Saha, T.
ID
ZDB-PUB-180125-4
Date
2018
Source
Chembiochem : a European journal of chemical biology   19(7): 723-735 (Journal)
Registered Authors
Pattanayak, Sankha, Sinha, Surajit
Keywords
Hedgehog inhibitors * small molecules * microtubule destabilizers * ciliogenesis * zebrafish
MeSH Terms
  • Animals
  • CHO Cells
  • Cell Cycle/drug effects
  • Cell Line, Tumor
  • Cilia/drug effects*
  • Cricetulus
  • Hedgehog Proteins/antagonists & inhibitors*
  • Humans
  • Indoles/chemical synthesis
  • Indoles/pharmacology*
  • Mice
  • Microtubules/drug effects*
  • Molecular Docking Simulation
  • NIH 3T3 Cells
  • Pyrimidines/chemical synthesis
  • Pyrimidines/pharmacology*
  • Signal Transduction/drug effects*
  • Swine
  • Tubulin/metabolism
  • Zebrafish
PubMed
29363254 Full text @ Chembiochem
Abstract
One of the crucial regulators of embryonic patterning and tissue development is the Hedgehog-Glioma (Hh-Gli) signaling pathway; however its uncontrolled activation has been implicated in different types of cancer in adult tissues. Primary cilium is one of the important factors required for the activation of Hh signaling, for it brings the critical components together for key protein-protein interactions required for Hh pathway regulation. Most of the synthetic and natural small molecule modulators of the pathway primarily antagonize Smoothened (Smo) or other effectors like Hh ligand or Gli. Here, we report a previously described Hh antagonist, with a pyrimidine-indole hybrid (PIH) core structure, as an inhibitor of ciliogenesis. The compound is unique in its mode of action for it shows perturbation of microtubule dynamics in both cell based assays and in vivo system (zebrafish embryos). Further studies reveal that the probable targets are alpha tubulin and its acetylated form found in the cytoplasm and primary cilia. It also shows axonal defasiculation in developing zebrafish embryos. We thus propose that PIH antagonizes Hh signaling by repressing cilia biogenesis and disassembly of alpha tubulin in its stabilized form.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping