Small-molecule WNK inhibition regulates cardiovascular and renal function

Yamada, Ken; Hm, Park; Df, Rigel; DiPetrillo, Keith; Ej, Whalen; Anisowicz, A; Beil, Michael E.; Berstler, James Douglas; Ce, Brocklehurst; Da, Burdick; Sl, Caplan; Mp, Capparelli; Chen, G; Chen, W; Dale, Brian; Deng, Lin; Fu, Fang; Hamamatsu, N; Harasaki, K; Herr, Thomas J; Hoffmann, Peter; Qy, Hu; Wj, Huang; Idamakanti, Neeraja; Imase, Hidetomo; Iwaki, Yuki; Jain, Mohit; Jeyaseelan, Jey R.; Kato, Mitsunori; Vk, Kaushik; Kohls, Darcy; Kunjathoor,; LaSala, Daniel; J, Lee; Liu, Jing; Luo, Yong; Mo, Ran; Mowbray, Sarah F.; Mogi, Muneto; Ossola, Flavio; Pandey, Pramod; Sj, Patel; Raghavan, Sarada; Salem, Bahaâ; Yh, Shanado; Gm, Trakshel; Turner, Gordon M.; Wakai, Hiromichi; Wang, C; Weldon, Steven M.; Jb, Wielicki; Xie, Xiao; Xu, Liang; Yi, Yagi; Yasoshima, Kayo; Yin, Jie; Yowe, David; Jh, Zhang; Zheng, Gui‐Hong; Monovich, Lauren G.

doi:10.1038/nchembio.2168

Cited by 138 publications

(165 citation statements)

References 28 publications

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“…First, we tested whether WNK kinase activity and not merely WNK1 presence is required for mRNA export by use of a pan-WNK kinase inhibitor called WNK463 (Yamada et al 2016). We confirmed WNK463 inhibition of WNK1 activity by showing that phosphorylation of a known WNK1 target, S325p of OSR1, was blocked by WNK463 treatment (Supplemental Fig.…”

Section: Pcf11 Cid Phosphorylation Mediates Mrna Exportmentioning

confidence: 62%

WNK1 kinase and the termination factor PCF11 connect nuclear mRNA export with transcription

et al. 2017

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Nuclear gene transcription is coordinated with transcript release from the chromatin template and messenger RNA (mRNA) export to the cytoplasm. Here we describe the role of nuclear-localized kinase WNK1 (with no lysine [K] 1) in the mammalian mRNA export pathway even though it was previously established as a critical regulator of ion homeostasis in the cytoplasm. Our data reveal that WNK1 phosphorylates the termination factor PCF11 on its RNA polymerase II (Pol II) C-terminal domain (CTD)-interacting domain (CID). Furthermore, phosphorylation of the PCF11 CID weakens its interaction with Pol II. We predict that WNK1 and the associated phosphorylation of the PCF11 CID act to promote transcript release from chromatin-associated Pol II. This in turn facilitates mRNA export to the cytoplasm.

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Section: Pcf11 Cid Phosphorylation Mediates Mrna Exportmentioning

confidence: 62%

WNK1 kinase and the termination factor PCF11 connect nuclear mRNA export with transcription

et al. 2017

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“…Among several crystal structures (PDB code: 3FPQ [6], 4PWN [7], 4Q2A [7], 5DRB [4], 5TF9 [5]) of WNK1 reported so far, we focused on 3FPQ-B ( Figure S1b), which possesses a deep back pocket and contains glycerols in the hinge region and at the bottom of the back pocket. Docking simulation targeting a glycerol at the bottom of the back pocket was performed with the MOE-Dock program in the Molecular Operating Environment (MOE) [8].…”

Section: Methodsmentioning

confidence: 99%

Docking simulation of fragment library compounds to find new leads for specific WNK kinase inhibitors

Saito

Tada

Okabe

et al. 2017

CBIJ

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Pseudohypoaldosteronism type II has been known as a rare autosomal dominant disorder caused by WNK1 [with no K (lysine) protein kinase-1] or WNK4. These serine/threonine kinases have unusual structures with a back pocket located just behind the ATP binding site. Moreover, a lysine residue (Lys233 in WNK1) in a glycine-rich loop plays a key role in their activity. In this work, we performed docking simulations of about 9,000 compounds from a fragment library with the back pocket of WNK1 in order to discover candidate lead compounds for development of specific inhibitors. Based on binding energy index, we selected -tetralone (compound 5) as a lead structure that interacts with the back pocket, but not with the hinge region of WNK1.Guided by the four predicted docking patterns of -tetralone with the back pocket, we designed four derivatives A-D that were expected to form hydrogen bonds with Lys233. Docking studies indicated that these derivatives interact selectively with Lys233, but not with the hinge region. These compounds are considered potential lead compounds for developing selective WNK inhibitors.

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“…Yamada et al tested WNK463 in a rat hypertension model (4). In spontaneously hypertensive rats, orally administered WNK463 significantly decreased blood pressure, increased urine output, and reduced the phosphorylation of SPAK and OSR1.…”

Section: P H a R M A C O L O G Ymentioning

confidence: 99%

Leveraging unique structural characteristics of WNK kinases to achieve therapeutic inhibition

Zhang

Deng

Kahle³

2016

Sci. Signal.

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Small-molecule WNK inhibition regulates cardiovascular and renal function

Cited by 138 publications

References 28 publications

WNK1 kinase and the termination factor PCF11 connect nuclear mRNA export with transcription

WNK1 kinase and the termination factor PCF11 connect nuclear mRNA export with transcription

Docking simulation of fragment library compounds to find new leads for specific WNK kinase inhibitors

Leveraging unique structural characteristics of WNK kinases to achieve therapeutic inhibition

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