Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein

Firestone, Ari J.; Weinger, Joshua S.; Maldonado, María; Barlan, Kari; Langston, Lance D.; O'Donnell, Mike; Gelfand, Vladimir I.; Kapoor, Tarun M.; Chen, James

doi:10.1038/nature10936

Cited by 359 publications

(420 citation statements)

References 30 publications

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“…This upregulation was blocked by pretreating cells with CBD, a small molecule which inhibits the dynein motor protein responsible for trafficking microtubules to primary cilia (Firestone et al, 2012). Notably, although CBD treatment reduces the size and number of primary cilia, it also regulates mitotic spindle formation and organelle transport (Firestone et al, 2012). Thus, our interpretation does not account for the possibility that our observed effects might result from non-specific effects of CBD.…”

Section: Discussionmentioning

confidence: 54%

“…We used an in vitro system to apply low-magnitude flow to endothelial cells to model endocardial, cilia-dependent flow responses and found that flow stimulated Notch1, Efnb2 and Nrg1 expression in the absence of myocardially derived factors or circulating factors in the bloodstream. This upregulation was blocked by pretreating cells with CBD, a small molecule which inhibits the dynein motor protein responsible for trafficking microtubules to primary cilia (Firestone et al, 2012). Notably, although CBD treatment reduces the size and number of primary cilia, it also regulates mitotic spindle formation and organelle transport (Firestone et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish

et al. 2015

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Congenital heart disease often features structural abnormalities that emerge during development. Accumulating evidence indicates a crucial role for cardiac contraction and the resulting fluid forces in shaping the heart, yet the molecular basis of this function is largely unknown. Using the zebrafish as a model of early heart development, we investigated the role of cardiac contraction in chamber maturation, focusing on the formation of muscular protrusions called trabeculae. By genetic and pharmacological ablation of cardiac contraction, we showed that cardiac contraction is required for trabeculation through its role in regulating notch1b transcription in the ventricular endocardium. We also showed that Notch1 activation induces expression of ephrin b2a (efnb2a) and neuregulin 1 (nrg1) in the endocardium to promote trabeculation and that forced Notch activation in the absence of cardiac contraction rescues efnb2a and nrg1 expression. Using in vitro and in vivo systems, we showed that primary cilia are important mediators of fluid flow to stimulate Notch expression. Together, our findings describe an essential role for cardiac contraction-responsive transcriptional changes in endocardial cells to regulate cardiac chamber maturation.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish

et al. 2015

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“…In contrast, CA2 disrupts cytoplasmic microtubules without affecting basal bodies. Ciliobrevin, a small molecule that inhibits ciliogenesis through the inhibition of cytoplasmic dynein, also disrupts microtubule organization and γ-tubulin localization (49).…”

Section: Discussionmentioning

confidence: 99%

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

Chen

Arkin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Vertebrate Hedgehog (Hh) signals involved in development and some forms of cancer, such as basal cell carcinoma, are transduced by the primary cilium, a microtubular projection found on many cells. A critical step in vertebrate Hh signal transduction is the regulated movement of Smoothened (Smo), a seven-transmembrane protein, to the primary cilium. To identify small molecules that interfere with either the ciliary localization of Smo or ciliogenesis, we undertook a high-throughput, microscopy-based screen for compounds that alter the ciliary localization of YFP-tagged Smo. This screen identified 10 compounds that inhibit Hh pathway activity. Nine of these Smo antagonists (SA1–9) bind Smo, and one (SA10) does not. We also identified two compounds that inhibit ciliary biogenesis, which block microtubule polymerization or alter centrosome composition. Differential labeling of cell surface and intracellular Smo pools indicates that SA1–7 and 10 specifically inhibit trafficking of intracellular Smo to cilia. In contrast, SA8 and 9 recruit endogenous Smo to the cilium in some cell types. Despite these different mechanisms of action, all of the SAs inhibit activation of the Hh pathway by an oncogenic form of Smo, and abrogate the proliferation of basal cell carcinoma-like cancer cells. The SA compounds may provide alternative means of inhibiting pathogenic Hh signaling, and our study reveals that different pools of Smo move into cilia through distinct mechanisms.

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“…On a basic science level, these membrane-permeable compounds provide the scientific community with a tool for the targeted and functional inhibition of a given protein in the cell; a potent means of evaluating the intracellular functions of that protein [1,2]. From a biomedical standpoint, the characterization of these small-molecule inhibitors affords an opportunity for the development of novel disease treatments centering on the repression of an offensive molecule or the reversal of its downstream effects [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Inhibitors of Myosin Proteins

et al. 2012

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Advances in screening and computational methods have enhanced recent efforts to discover/ design small-molecule protein inhibitors. One attractive target for inhibition is the myosin family of motor proteins. Myosins function in a wide variety of cellular processes, from intracellular trafficking to cell motility, and are implicated in several human diseases (e.g., cancer, hypertrophic cardiomyopathy, deafness and many neurological disorders). Potent and selective myosin inhibitors are, therefore, not only a tool for understanding myosin function, but are also a resource for developing treatments for diseases involving myosin dysfunction or overactivity. This review will provide a brief overview of the characteristics and scientific/therapeutic applications of the presently identified small-molecule myosin inhibitors before discussing the future of myosin inhibitor and activator design.The identification and characterization of pharmacological compounds that inhibit the functional activity of one or more specific proteins or processes has been the subject of much scientific investigation. On a basic science level, these membrane-permeable compounds provide the scientific community with a tool for the targeted and functional inhibition of a given protein in the cell; a potent means of evaluating the intracellular functions of that protein [1,2]. From a biomedical standpoint, the characterization of these small-molecule inhibitors affords an opportunity for the development of novel disease treatments centering on the repression of an offensive molecule or the reversal of its downstream effects [3][4][5].At present, several complementary methods for obtaining suitable small-molecule inhibitors of specific proteins exist. Traditional methods in inhibitor discovery involve the systematic testing of a series of chemically synthesized or naturally occurring compounds. Advances in robotics and data processing have made it possible to use high-throughput screens to test libraries of thousands or even millions of potential drugs for their ability to inhibit the function of a specific protein in a targeted biochemical or cellular assay [6][7][8]. These inhibitor discovery processes are complemented by more precise methods in small-molecule inhibitor design. Structure-based methods rely on the use of x-ray crystallographic or NMRbased structures of a protein of interest to design small molecules likely to bind and inhibit protein function [9,10]. Computer-aided inhibitor design uses computational methods to optimize potential inhibitors identified by screening or structure-based methods, to virtually © 2013 Folma Buss * Author for correspondence: Tel.: +44 1223 763348, Fax: +44 1223 762640, fb207@cam.ac.uk. Financial & competing interests disclosureThe authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance w...

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Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein

Cited by 359 publications

References 30 publications

Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish

Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish

Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis

Small-Molecule Inhibitors of Myosin Proteins

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