The Imidazopyridine Derivative JK184 Reveals Dual Roles for Microtubules in Hedgehog Signaling

Cupido, Tommaso; Rack, Paul G.; Firestone, Ari J.; Hyman, Joel M.; Han, Ke; Sinha, Surajit; Ocasio, Cory A.; Chen, James

doi:10.1002/ange.200805666

Cited by 16 publications

(16 citation statements)

References 24 publications

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“…Compound 36 was recently shown to block Hh target gene expression in SuFu −/− murine embryonic fibroblasts (MEFs), demonstrating that it acts downstream of SuFu, i.e., at the level of the Gli transcription factors 91. It was also found to inhibit guanosine triphosphate (GTP)‐initiated microtubule polymerization with a potency consistent with its IC 50 value in Shh signaling assays.…”

Section: Other Hh Pathway Inhibitorsmentioning

confidence: 82%

Small‐Molecule Inhibitors of the Hedgehog Signaling Pathway as Cancer Therapeutics

Peukert¹,

2010

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Inhibitors of the Hedgehog (Hh) molecular signaling pathway have emerged in recent years as a promising new class of potential therapeutics for cancer treatment. Numerous drug discovery efforts have resulted in the identification of a wide variety of small molecules that target different members of this pathway, including Smoothened (Smo), Sonic hedgehog protein (Shh), and Gli1. Several Smo inhibitors have now entered human clinical trials, and successful proof‐of‐concept studies have been carried out in patients with defined genetic mutations in the Hh pathway. This review provides a general overview of three main topics in this rapidly expanding area: 1) the various types of biological assays and in vivo models that have been employed for the identification and optimization of Hh pathway inhibitors; 2) Smo inhibitors reported to date, including recent clinical results where available; and 3) efforts toward the identification and characterization of inhibitors of other members of the Hh pathway.

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Section: Other Hh Pathway Inhibitorsmentioning

confidence: 82%

Small‐Molecule Inhibitors of the Hedgehog Signaling Pathway as Cancer Therapeutics

Peukert¹,

2010

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“…Target validation was then performed using an in vitro tubulin polymerization assay. As shown in Figure 5 a, compound 1 inhibited tubulin polymerization in a dose‐dependent manner and showed a similar activity to nocodazole,13 a known tubulin polymerization inhibitor. Even at 100 n M , compound 1 still showed some inhibition of tubulin polymerization.…”

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confidence: 72%

Discovery and Target Identification of an Antiproliferative Agent in Live Cells Using Fluorescence Difference in Two‐Dimensional Gel Electrophoresis

Park

2012

Angewandte Chemie

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Ziel gefunden: Durch Fluoreszenzdifferenz in der 2D‐Gelelektrophorese (FITGE) können Wechselwirkungen zwischen Proteinen und Wirkstoffmolekülen in intakter zellulärer Umgebung beobachtet werden. Wo konventionelle Methoden keinen Erfolg hatten, gelang mit FITGE die Identifizierung des Zielproteins einer antiproliferativen Verbindung in lebenden Zellen durch Differenzierung zwischen spezifischer und unspezifischer Bindung von Photoaffinitätssonden.

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“…Ciliobrevin, a known cytoplasmic dynein antagonist, abrogates microtubule assembly and γ‐tubulin localisation. Upon treatment with JK184, a potent microtubule inhibitor, cilia in some cells exhibit abnormal morphologies. Also, this compound induces nuclear fragmentation similar to nocodazole, which was not seen with our PIH compound.…”

Section: Resultsmentioning

confidence: 99%

“…Pelleted fractions were resuspended in an equal volume of buffer and 15 μL of the resulting supernatant, and the pelleted fractions were then boiled with 1× SDS‐PAGE loading buffer (50 m m Tris ⋅ HCl, pH 6.8 containing 10 % glycerol, 2 % SDS, 50 m m DTT, 200 m m 2‐mercaptoethanol and 0.001 % Bromophenol Blue) for 5 min. The samples were then separated by electrophoresis in a 12 % SDS‐PAGE system and stained with Coomassie Brilliant Blue …”

Section: Methodsmentioning

confidence: 99%

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Hedgehog Antagonist Pyrimidine–Indole Hybrid Molecule Inhibits Ciliogenesis through Microtubule Destabilisation

et al. 2018

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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 α-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 α-tubulin from its stabilised form.

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The Imidazopyridine Derivative JK184 Reveals Dual Roles for Microtubules in Hedgehog Signaling

Cited by 16 publications

References 24 publications

Small‐Molecule Inhibitors of the Hedgehog Signaling Pathway as Cancer Therapeutics

Small‐Molecule Inhibitors of the Hedgehog Signaling Pathway as Cancer Therapeutics

Discovery and Target Identification of an Antiproliferative Agent in Live Cells Using Fluorescence Difference in Two‐Dimensional Gel Electrophoresis

Hedgehog Antagonist Pyrimidine–Indole Hybrid Molecule Inhibits Ciliogenesis through Microtubule Destabilisation

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