Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: UNIPROT:Q86TM3 (
cage
)
29,987
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Continuous exposure of a pancreatic cancer cell line MIA PaCa-2 (Mia
S
) to gemcitabine resulted in the formation of a gemcitabine-resistant subline (Mia
R
). In an effort to discover kinase inhibitors that inhibited Mia
R
growth, Mia
R
cells were exposed to kinase inhibitors (PKIS-1 library) in a 384-well screening format. Three compounds (UNC10112721A, UNC10112652A, and UNC10112793A) were identified that inhibited the growth of Mia
R
cells by more than 50% (at 50 nM). Two compounds (UNC10112721A and UNC10112652A) were classified as cyclin-dependent kinase (CDK) inhibitors, whereas UNC10112793A was reported to be a PLK inhibitor. Dose-response experiments supported the efficacy of these compounds to inhibit growth and increase apoptosis in 2D cultures of these cells. However, only UNC10112721A significantly inhibited the growth of 3D spheroids composed of Mia
R
cells and GFP-tagged
cancer-associated
fibroblasts. Multiplexed inhibitor bead (MIB)-mass spectrometry (MS) kinome competition experiments identified CDK9,
CLK1
-4, DYRK1A, and CSNK1 as major kinase targets for UNC10112721A in Mia
R
cells. Another CDK9 inhibitor (CDK-IN-2) replicated the growth inhibitory effects of UNC10112721A, whereas inhibitors against the CLK, DYRK, or CSNK1 kinases had no effect. In summary, these studies describe a coordinated approach to discover novel kinase inhibitors, evaluate their efficacy in 3D models, and define their specificity against the kinome.
...
PMID:Application of Integrated Drug Screening/Kinome Analysis to Identify Inhibitors of Gemcitabine-Resistant Pancreatic Cancer Cell Growth. 2974 58
Alternative splicing is a key process required for the regulation of gene expression in normal development and physiology. It is regulated by splice factors whose activities are in turn regulated by splice factor kinases and phosphatases. The CDC-like protein kinases are a widespread family of splice factor kinases involved in normal physiology and in several diseases including cancer. In humans they include the
CLK1
, CLK2, CLK3 and CLK4 genes. The expression of
CLK1
is regulated through alternative splicing producing both full-length catalytically active and truncated catalytically inactive isoforms, CLK
T1
(arising from exon 4 skipping) and CLK
T2
(arising from intron 4 retention). We examined
CLK1
alternative splicing in a range of cancer cell lines, and report widespread and highly variable rates of exon 4 skipping and intron 4 retention. We also examined the effect of severe environmental stress including heat shock, osmotic shock, and exposure to the alkaloid drug harmine on
CLK1
alternative splicing in DU145 prostate cancer cells. All treatments rapidly reduced exon 4 skipping and intron 4 retention, shifting the balance towards full-length
CLK1
expression. We also found that the inhibition of
CLK1
with the benzothiazole TG003 reduced exon 4 skipping and intron 4 retention suggesting an autoregulatory mechanism.
CLK1
inhibition with TG003 also resulted in modified alternative splicing of five
cancer-associated
genes.
...
PMID:Autoregulation of the human splice factor kinase CLK1 through exon skipping and intron retention. 2980 95
