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Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
TLDR
It is shown that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3, and it is demonstrated that PKB is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC).
AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.
TLDR
A novel structurally distinct third-generation EGFR TKI that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR is reported.
Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity
TLDR
Osimertinib may represent a clinically significant treatment option for patients with EGFRm NSCLC and brain metastases and early clinical evidence of osimertinIB activity in previously treated patients withEGFRm-advanced NSCLc and brain Metastases is reported.
Characterization of VPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding SGK3 protein kinase is a downstream target of class III phosphoinositide
TLDR
A highly selective and potent inhibitor of Vps34, termed VPS34-IN1, is described that inhibits Vps 34 with 25 nM IC50 in vitro, but does not significantly inhibit the activity of 340 protein kinases or 25 lipid kinases tested that include all isoforms of class I as well as class II PI3Ks.
Selective small‐molecule inhibitors of glycogen synthase kinase‐3 activity protect primary neurones from death
TLDR
The data provide clear pharmacological and biochemical evidence that selective inhibition of the endogenous pool of GSK‐3 activity in primary neurones is sufficient to prevent death, implicating G SK‐3 as a physiologically relevant principal regulatory target of the PI’3‐kinase/PKB neuronal survival pathway.
ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK
TLDR
It is shown directly that, like ATM and DNA-PK, ATR phosphorylates the genome surveillance protein p53 on serine 15, a site which is up-regulated in response to DNA damage, suggesting that these proteins have overlapping but distinct functions in vivo.
Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background
TLDR
It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS.
Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor.
TLDR
Following observations of significant tumor inhibition in preclinical models, the clinical candidate AZD9291 was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
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