Title | Chemical structure-guided design of dynapyrazoles, cell-permeable dynein inhibitors with a unique mode of action. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Steinman JB, Santarossa CC, Miller RM, Yu LS, Serpinskaya AS, Furukawa H, Morimoto S, Tanaka Y, Nishitani M, Asano M, Zalyte R, Ondrus AE, Johnson AG, Ye F, Nachury MV, Fukase Y, Aso K, Foley MA, Gelfand VI, Chen JK, Carter AP, Kapoor TM |
Journal | Elife |
Volume | 6 |
Date Published | 2017 05 19 |
ISSN | 2050-084X |
Keywords | Crystallography, X-Ray, Dyneins, Enzyme Inhibitors, Humans, Molecular Structure, Pyrazoles, Quinazolinones |
Abstract | 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. |
DOI | 10.7554/eLife.25174 |
Alternate Journal | Elife |
PubMed ID | 28524820 |
PubMed Central ID | PMC5478271 |
Grant List | R21 HD087126 / HD / NICHD NIH HHS / United States R01 GM052111 / GM / NIGMS NIH HHS / United States MC_UP_A025_1011 / / Medical Research Council / United Kingdom R01 GM098579 / GM / NIGMS NIH HHS / United States R01 GM113100 / GM / NIGMS NIH HHS / United States / / Wellcome Trust / United Kingdom S10 OD016320 / OD / NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States R01 GM089933 / GM / NIGMS NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:10pm