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Chemical structure-guided design of dynapyrazoles, potent cell-permeable dynein inhibitors with a unique mode of action

Steinman, Jonathan B. and Santarossa, Cristina C. and Miller, Rand M. and Yu, Lola S. and Serpinskaya, Anna S. and Furukawa, Hideki and Morimoto, Sachie and Tanaka, Yuta and Nishitani, Mitsuyoshi and Asano, Moriteru and Zalyte, Ruta and Ondrus, Alison E. and Johnson, Alex G. and Ye, Fan and Nachury, Maxence V. and Fukase, Yoshiyuki and Aso, Kazuyoshi and Foley, Michael A. and Gelfand, Vladimir I. and Chen, James K. and Carter, Andrew P. and Kapoor, Tarun M. (2017) Chemical structure-guided design of dynapyrazoles, potent cell-permeable dynein inhibitors with a unique mode of action. eLife, 6 . Art. No. e25174. ISSN 2050-084X. PMCID PMC5478271. doi:10.7554/eLife.25174.

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Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has in part been limited by low potency. Moreover, suboptimal chemical properties, such as the potential to isomerize, have hindered efforts to improve ciliobrevins. Here, we characterized the structure of ciliobrevins and designed conformationally constrained isosteres. These studies identified dynapyrazoles, inhibitors more potent than ciliobrevins. At single-digit micromolar concentrations dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Further, we find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles strongly block only microtubule-stimulated activity. Together, our studies suggest that chemical-structure-based analyses can lead to inhibitors with improved properties and distinct modes of inhibition.

Item Type:Article
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URLURL TypeDescription CentralArticle
Steinman, Jonathan B.0000-0001-9492-4746
Ondrus, Alison E.0000-0002-6023-3290
Kapoor, Tarun M.0000-0003-0628-211X
Additional Information:© 2017 Steinman et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited. Received January 20, 2017. Accepted May 17, 2017. Published May 19, 2017. We thank Professor Erwin Peterman and Dr. Pierre Mangeol for assistance with analysis of intraflagellar transport data. We acknowledge Mr. M Iida (Takeda Pharmaceuticals Company, Limited, Kanagawa, Japan) for valuable assistance with structural analysis of compounds. We thank Dr. Milica Tesic Mark and Dr. Henrik Molina (Rockefeller University) for assistance with mass spectrometry. This work was supported by the NIH (R01 GM098579 to TMK, R01 GM52111 to VIG, R01 GM113100 to JKC, and R01 GM089933 to MVN). TMK acknowledges the Robertson Therapeutic Development Fund for support. JBS was supported by NIH grant T32GM007739 to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. RMM was supported by a Damon Runyon Cancer Research Foundation Postdoctoral Fellowship (DRG-2222–15). APC was supported by the Medical Research Council, UK (MC_UP_A025_1011) and a Wellcome Trust New Investigator Award (WT100387). The WCMC NMR facility was supported by NIH instrumentation grant S10 OD016320. The Proteomics Resource Center at The Rockefeller University was supported by Leona M and Harry B Helmsley Charitable Trust for mass spectrometer instrumentation. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Funding AgencyGrant Number
NIHR01 GM098579
NIHR01 GM52111
NIHR01 GM113100
NIHR01 GM089933
Robertson Therapeutic Development FundUNSPECIFIED
NIH Predoctoral FellowshipT32GM007739
Damon Runyon Cancer Research FoundationDRG-2222-15
Medical Research Council (UK)MC_UP_A025_1011
Wellcome TrustWT100387
NIHS10 OD016320
Leona M. and Harry B. Helmsley Charitable TrustUNSPECIFIED
PubMed Central ID:PMC5478271
Record Number:CaltechAUTHORS:20170523-075555486
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:77646
Deposited By: Tony Diaz
Deposited On:23 May 2017 18:26
Last Modified:25 Apr 2022 20:47

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