scholarly journals A new lead to NLRP3 inhibition

2017 ◽  
Vol 214 (11) ◽  
pp. 3147-3149 ◽  
Author(s):  
Mohamed Lamkanfi ◽  
Vishva M. Dixit
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Therapeutic Benefit ◽  
Human Diseases ◽  
Molecule Inhibitor ◽  
Wide Range ◽  
Potential Therapeutic Benefit

The discovery of a small molecule inhibitor that targets the inflammasome sensor NLRP3 offers a new path for the development of selective inflammasome blockers with potential therapeutic benefit in a wide range of human diseases (in this issue, see Jiang et al., https://doi.org/10.1084/jem.20171419).

scholarly journals A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma

Blood ◽  
2010 ◽  
Vol 115 (4) ◽  
pp. 824-833 ◽  
Author(s):  
Ying-Wei Lin ◽  
Zanna M. Beharry ◽  
Elizabeth G. Hill ◽  
Jin H. Song ◽  
Wenxue Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinases ◽  
Small Molecule ◽  
Lymphoblastic Leukemia ◽  
Small Molecule Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Phase Cell ◽  
Pim Kinases ◽  
Molecule Inhibitor ◽  
Wide Range

Abstract The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre–T-LBL/T-ALL) being highly sensitive. Incubation of pre–T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre–T-LBL cells. In immunodeficient mice carrying subcutaneous pre–T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre–T-LBL.

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