更新于：2024-11-01

PIP4K2A x PIP4K2C x PIP4K2B

更新于：2024-11-01

基本信息

关联

项与 PIP4K2A x PIP4K2C x PIP4K2B 相关的药物

TM-04-168-03

靶点

PIP4K2A x PIP4K2B x PIP4K2C

作用机制

PIP4K2A抑制剂 [+2]

在研机构-

原研机构-

在研适应症-

非在研适应症-

最高研发阶段-

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PIP4K2A x PIP4K2C x PIP4K2B 相关的临床结果

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100 项与 PIP4K2A x PIP4K2C x PIP4K2B 相关的转化医学

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0 项与 PIP4K2A x PIP4K2C x PIP4K2B 相关的专利（医药）

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项与 PIP4K2A x PIP4K2C x PIP4K2B 相关的文献（医药）

2024-08-01·European Journal of Pharmacology

Potency and efficacy of pharmacological PIP4K2 inhibitors in acute lymphoblastic leukemia

Article

作者: Machado-Neto, João Agostinho ; Lima, Keli ; Velloso, Elvira Deolinda Rodrigues Pereira ; da Silva, Wellington Fernandes ; Cipelli, Marcella ; Leal, Aline de Medeiros ; Schuringa, Jan Jacob ; Câmara, Niels Olsen Saraiva ; Pereira-Martins, Diego Antonio ; Nogueira, Frederico Lisboa ; Carvalho, Maria Fernanda Lopes ; Nardinelli, Luciana ; Bendit, Israel ; Cavaglieri, Rita de Cássia ; Rego, Eduardo Magalhães

Acute lymphoblastic leukemia (ALL), a complex malignancy, displays varying expression profiles of PIP4K2-related genes in adult patients. While PIP4K2A expression is elevated in ALL bone marrow cells compared to healthy bone marrow cells, PIP4K2B is downregulated, and PIP4K2C remains relatively unchanged. Despite the correlation between increased PIP4K2A expression and increased percentage of peripheral blood blasts, clinical outcomes do not strongly correlate with the expression of these genes. Here we investigated the therapeutic potential of three PIP4K2 inhibitors (THZ-P1-2, a131, and CC260) in ALL cell models. THZ-P1-2 emerges as the most effective inhibitor, inducing cell death and mitochondrial damage while reducing cell viability and metabolism significantly. Comparative analyses highlight the superior efficacy of THZ-P1-2 over a131 and CC260. Notably, THZ-P1-2 uniquely disrupts autophagic flux and inhibits the PI3K/AKT/mTOR pathway, indicating a distinct molecular mechanism. In summary, our findings elucidate the differential expression of PIP4K2-related genes in ALL and underscore the potential role of PIP4K2A in disease pathogenesis. The therapeutic promise of THZ-P1-2 in ALL treatment, along with its distinct effects on cell death mechanisms and signaling pathways, enriches our understanding of PIP4K2's involvement in ALL development and offers targeted therapy prospects.

2021-02-01·Journal of Comparative Neurology3区 · 医学

Distribution and localization of phosphatidylinositol 5‐phosphate, 4‐kinase alpha and beta in the brain

3区 · 医学

Article

作者: Cantley, Lewis C. ; Milner, Teresa A. ; Noch, Evan K. ; Yim, Isaiah

AbstractPhosphatidylinositol‐4,5‐bisphosphate (PI‐4,5‐P2) is critical for synaptic vesicle docking and fusion and generation of the second messengers, diacylglycerol and inositol‐1,4,5‐trisphosphate. PI‐4,5‐P2 can be generated by two families of kinases: type 1 phosphatidylinositol‐4‐phosphate 5‐kinases, encoded by PIP5K1A, PIP5K1B and PIP5K1C, and type 2 phosphatidylinositol‐5‐phosphate 4‐kinases, encoded by PIP4K2A, PIP4K2B, and PIP4K2C. While the roles of the type 1 enzymes in brain function have been extensively studied, the roles of the type 2 enzymes are poorly understood. Using selective antibodies validated by genetic deletion of pip4k2a or pip4k2b in mouse brain, we characterized the location of the enzymes, PI5P4Kα and PI5P4Kβ, encoded by these genes. In mice, we demonstrate that PI5P4Kα is expressed in adulthood, whereas PI5P4Kβ is expressed early in development. PI5P4Kα localizes to white matter tracts, especially the corpus callosum, and at a low level in neurons, while PI5P4Kβ is expressed in neuronal populations, especially hippocampus and cortex. Dual labeling studies demonstrate that PI5P4Kα co‐localizes with the oligodendrocyte marker, Olig2, whereas PI5P4Kβ co‐localizes with the neuronal marker, NeuN. Ultrastructural analysis demonstrates that both kinases are contained in axon terminals and dendritic spines adjacent to the synaptic membrane, which support a potential role in synaptic transmission. Immunoperoxidase analysis of macaque and human brain tissue demonstrate a conserved pattern for PI5P4Kα and PI5P4Kβ. These results highlight the diverse cell‐autonomous expression of PI5P4Kα and PI5P4Kβ and support further exploration into their role in synaptic function in the brain.

2019-05-01·Cell Reports1区 · 生物学

PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism

1区 · 生物学

ArticleOA

作者: Cindy Hodakoski ; Lukas E. Dow ; Diana G. Wang ; Solomon Amadiume ; Jeremy M. Baskin ; Marcia N. Paddock ; Mark R. Lundquist ; Matthew Fine ; Amanda Hill ; T. Jonathan Yang ; Timothy W. Bumpus ; Oksana Mashadova ; Benjamin D. Hopkins ; Lewis C. Cantley ; Janet Y. Sun

Insulin stimulates the conversion of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P₂) to phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P₃), which mediates downstream cellular responses. PI(4,5)P₂ is produced by phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) and by phosphatidylinositol-5-phosphate 4-kinases (PIP4Ks). Here, we show that the loss of PIP4Ks (PIP4K2A, PIP4K2B, and PIP4K2C) in vitro results in a paradoxical increase in PI(4,5)P₂ and a concomitant increase in insulin-stimulated production of PI(3,4,5)P₃. The reintroduction of either wild-type or kinase-dead mutants of the PIP4Ks restored cellular PI(4,5)P₂ levels and insulin stimulation of the PI3K pathway, suggesting a catalytic-independent role of PIP4Ks in regulating PI(4,5)P₂ levels. These effects are explained by an increase in PIP5K activity upon the deletion of PIP4Ks, which normally suppresses PIP5K activity through a direct binding interaction mediated by the N-terminal motif VMLΦPDD of PIP4K. Our work uncovers an allosteric function of PIP4Ks in suppressing PIP5K-mediated PI(4,5)P₂ synthesis and insulin-dependent conversion to PI(3,4,5)P₃ and suggests that the pharmacological depletion of PIP4K enzymes could represent a strategy for enhancing insulin signaling.