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Small-molecule WNK inhibition regulates cardiovascular and renal function

Abstract

The With-No-Lysine (K) (WNK) kinases play a critical role in blood pressure regulation and body fluid and electrolyte homeostasis. Herein, we introduce the first orally bioavailable pan-WNK-kinase inhibitor, WNK463, that exploits unique structural features of the WNK kinases for both affinity and kinase selectivity. In rodent models of hypertension, WNK463 affects blood pressure and body fluid and electro-lyte homeostasis, consistent with WNK-kinase-associated physiology and pathophysiology.

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Figure 1: WNK463 is a pan-WNK-kinase inhibitor that exploits the unusual structure of the WNK kinase domain.
Figure 2: WNK463 affects blood pressure and electrolyte excretion in vivo.

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Protein Data Bank

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GenBank/EMBL/DDBJ

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Acknowledgements

The authors acknowledge G. Waters and L.D. Morton for careful reading of this manuscript and K. Gunderson for detailed NMR analysis of WNK463 (Novartis Institutes for BioMedical Research). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

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K.Yamada, D.F.R., K.D., E.J.W. and L.M. prepared the manuscript. H.-M.P., E.J.W. and L.M. directed drug discovery experiments, D.F.R. and K.D. in vivo experiments, and J.-H.Z. the high-throughput screen. K.Yamada, H.-M.P. and M.M. designed the hit-finding strategy. K.Yamada, M.P.C., Q.-Y.H., H.I., Y.I., F.M., R.M., S.J.P., B.S., K.Yasoshima and L.M. performed chemical synthesis and developed structure–activity relationship. M.K. developed and performed computational model for structure-based design. C.E.B. and F.O. performed scale-up synthesis for in vivo studies. D.K. and X.X. performed biophysical and X-ray studies. H.-M.P., J.B., G.C., B.D., V.K.K., D.L., S.R., Y.H.S. and Y.I.Y. developed and/or performed biochemical assays. H.-M.P., E.J.W., W.-J.H., N.I., J.J., Y.L., S.M., J.Y., D.Y., G.Z. and Y.I.Y. developed and/or performed cellular assays. D.F.R., K.D., M.B., W.C., F.F., T.H., J. Liu and L.X. developed and/or performed in vivo experiments. K.D., E.J.W., K.H., V.K., G.T. and J.Y. designed and/or performed tissue pharmacodynamic analysis. P.H. directed toxicology studies with WNK463. A.A., D.A.B., S.L.C., N.H., J. Lee, P.P., G.M.T., H.W., C.W. and S.W. produced proteins for biochemical, biophysical and X-ray studies. L.D. and M.J. performed pharmacokinetic studies and J.B.W. prepared formulations for in vivo compound screening.

Corresponding author

Correspondence to Ken Yamada.

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Competing interests

All authors were employed by Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA, during the period of their research described in this manuscript. All research was fully funded by Novartis.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–3, Supplementary Figures 1–5 and Supplementary Note. (PDF 2059 kb)

Supplementary Data Set

Kinase selectivity data based on KINOMEscan from Ambit Biosciences (XLSX 25 kb)

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Yamada, K., Park, HM., Rigel, D. et al. Small-molecule WNK inhibition regulates cardiovascular and renal function. Nat Chem Biol 12, 896–898 (2016). https://doi.org/10.1038/nchembio.2168

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