Journal
CHEMBIOCHEM
Volume 19, Issue 7, Pages 723-735Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201700631
Keywords
ciliogenesis; Hedgehog inhibitors; microtubule destabilizers; small molecules; zebrafish
Funding
- Science and Engineering Research Board, Department of Science and Technology, Government of India, New Delhi [SR/S1/OC/0087/2012]
- Indian Association for the Cultivation of Science (IACS)
- Council of Scientific and Industrial Research (CSIR), New Delhi
- DBT
- Wellcome Trust/DBT India project
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One of the crucial regulators of embryonic patterning and tissue development is the Hedgehog-glioma (Hh-Gli) signalling pathway; 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 signalling, as 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 antagonise 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, as it shows perturbation of microtubule dynamics in both cell-based assays and in vivo systems (zebrafish embryos). Further studies revealed that the probable targets are -tubulin and its acetylated form, found in the cytoplasm and primary cilia. PIH also showed axonal defasiculation in developing zebrafish embryos. We thus propose that PIH antagonises Hh signalling by repressing cilia biogenesis and disassembling -tubulin from its stabilised form.
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