The SLC12A cation-Cl − cotransporters (CCC), including NKCC1 and the KCCs, are important determinants of brain ionic homeostasis. SPAK kinase (STK39) is the CCC master regulator, which stimulates NKCC1 ionic influx and inhibits KCC-mediated efflux via phosphorylation at conserved, shared motifs. Upregulation of SPAK-dependent CCC phosphorylation has been implicated in several neurological diseases. Using a scaffold-hybrid strategy, we develop a novel potent and selective SPAK inhibitor, 5-chloro-N-(5-chloro-4-((4-chlorophenyl)(cyano) methyl)-2-methylphenyl)-2-hydroxybenzamide ("ZT-1a"). ZT-1a inhibits NKCC1 and stimulates KCCs by decreasing their SPAK-dependent phosphorylation. Intracerebroventricular delivery of ZT-1a decreases inflammation-induced CCC phosphorylation in the choroid plexus and reduces cerebrospinal fluid (CSF) hypersecretion in a model of post-hemorrhagic hydrocephalus. Systemically administered ZT-1a reduces ischemia-induced CCC phosphorylation, attenuates cerebral edema, protects against brain damage, and improves outcomes in a model of stroke. These results suggest ZT-1a or related compounds may be effective CCC modulators with therapeutic potential for brain disorders associated with impaired ionic homeostasis.

Highlights d STK19 phosphorylates and activates oncogenic NRAS to promote melanomagenesis d We developed a novel potent and selective STK19 inhibitor, ZT-12-037-01 (1a) d ZT-12-037-01 (1a) inhibits NRAS-driven melanomagenesis and melanoma growth

No abstract

SUMMARY The Wnt/β-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of β-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic β-catenin pathway for cancer therapy, development of specific inhibitors remains insufficient. Using a T-cell factor (TCF)-dependent luciferase-reporter system, we screen for small molecule compounds that act against Wnt/β-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenyl)sulfonyl]amino}benzoate) as a selective inhibitor of Wnt/β-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to β-catenin promoting its degradation, and specifically downregulates Wnt/β-catenin target genes. Our findings might represent an effective strategy for cancers addicted to the Wnt/β-catenin signaling pathway.

In this paper, we study the three-dimensional axisymmetric Navier-Stokes system with nonzero swirl. By establishing a new key inequality for the pair ( ω r r , ω θ r ), we get several Prodi-Serrin type regularity criteria based on the angular velocity, u θ . Moreover, we obtain the global well-posedness result if the initial angular velocity u θ 0 is appropriate small in the critical space L 3 (R 3 ). Furthermore, we also get several Prodi-Serrin type regularity criteria based on one component of the solutions, say ω 3 or u 3 .